Inhibitors of protein tyrosine kinase activity

ABSTRACT

This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling. The invention also provides compounds, compositions and methods for treating cell proliferative diseases and conditions and opthalmological diseases, disorders and conditions.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/920,676, filed Sep. 2, 2010, which is a U.S. National StageApplicantion based on International Application PCT/CA2009/000228, filedon Feb. 27, 2009, which claims the benefit of U.S. ProvisionalApplication Ser. No. 61/034,005, filed Mar. 5, 2008. The entireteachings of the above-referenced application is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds that inhibit protein tyrosine kinaseactivity. In particular the invention relates to compounds that inhibitthe protein tyrosine kinase activity of growth factor receptors,resulting in the inhibition of receptor signaling, for example, theinhibition of VEGF receptor signaling and HGF receptor signaling. Moreparticularly, the invention relates to compounds, compositions andmethods for the inhibition of VEGF receptor signaling and HGF receptorsignaling.

2. Summary of the Related Art

Tyrosine kinases may be classified as growth factor receptor (e.g. EGFR,PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases.The receptor type tyrosine kinases make up about 20 differentsubfamilies. The non-receptor type tyrosine kinases make up numeroussubfamilies. These tyrosine kinases have diverse biological activity.Receptor tyrosine kinases are large enzymes that span the cell membraneand possess an extracellular binding domain for growth factors, atransmembrane domain, and an intracellular portion that functions as akinase to phosphorylate a specific tyrosine residue in proteins andhence to influence cell proliferation. Aberrant or inappropriate proteinkinase activity can contribute to the rise of disease states associatedwith such aberrant kinase activity.

Angiogenesis is an important component of certain normal physiologicalprocesses such as embryogenesis and wound healing, but aberrantangiogenesis contributes to some pathological disorders and inparticular to tumor growth. VEGF-A (vascular endothelial growth factorA) is a key factor promoting neovascularization (angiogenesis) oftumors. VEGF induces endothelial cell proliferation and migration bysignaling through two high affinity receptors, the fms-like tyrosinekinase receptor, Flt-1, and the kinase insert domain-containingreceptor, KDR. These signaling responses are critically dependent uponreceptor dimerization and activation of intrinsic receptor tyrosinekinase (RTK) activity. The binding of VEGF as a disulfide-linkedhomodimer stimulates receptor dimerization and activation of the RTKdomain. The kinase activity autophosphorylates cytoplasmic receptortyrosine residues, which then serve as binding sites for moleculesinvolved in the propagation of a signaling cascade. Although multiplepathways are likely to be elucidated for both receptors, KDR signalingis most extensively studied, with a mitogenic response suggested toinvolve ERK-1 and ERK-2 mitogen-activated protein kinases.

Disruption of VEGF receptor signaling is a highly attractive therapeutictarget in cancer, as angiogenesis is a prerequisite for all solid tumorgrowth, and that the mature endothelium remains relatively quiescent(with the exception of the female reproductive system and woundhealing). A number of experimental approaches to inhibiting VEGFsignaling have been examined, including use of neutralizing antibodies,receptor antagonists, soluble receptors, antisense constructs anddominant-negative strategies.

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibitionalone, several issues may limit this approach. VEGF expression levelscan themselves be elevated by numerous diverse stimuli and perhaps mostimportantly, the hypoxic state of tumors resulting from VEGFrinhibition, can lead to the induction of factors that themselves promotetumor invasion and metastasis thus, potentially undermining the impactof VEGF inhibitors as cancer therapeutics

The HGF (hepatocyte growth factor) and the HGF receptor, c-met, areimplicated in the ability of tumor cells to undermine the activity ofVEGF inhibition. HGF derived from either stromal fibroblasts surroundingtumor cells or expressed from the tumor itself has been suggested toplay a critical role in tumor angiogenesis, invasion and metastasis. Forexample, invasive growth of certain cancer cells is drastically enhancedby tumor-stromal interactions involving the HGF/c-Met (HGF receptor)pathway. HGF, which was originally identified as a potent mitogen forhepatocytes is primarily secreted from stromal cells, and the secretedHGF can promote motility and invasion of various cancer cells thatexpress c-Met in a paracrine manner. Binding of HGF to c-Met leads toreceptor phosphorylation and activation of Ras/mitogen-activated proteinkinase (MAPK) signaling pathway, thereby enhancing malignant behaviorsof cancer cells. Moreover, stimulation of the HGF/c-met pathway itselfcan lead to the induction of VEGF expression, itself contributingdirectly to angiogenic activity.

Thus, anti-tumor anti-angiogenic strategies or approaches that targetVEGF/VEGFr signaling or HGF/c-met signaling may represent improvedcancer therapeutics.

Tyrosine kinases also contribute to the pathology of opthalmologicaldiseases, disorders and conditions, such as age-related maculardegeneration (AMD) and diabetic retinopathy (DR). Blindness from suchdiseases has been linked to anomalies in retinal neovascularization. Theformation of new blood vessels is regulated by growth factors such asVEGF and HGF that activate receptor tyrosine kinases resulting in theinitiation of signaling pathways leading to plasma leakage into themacula, causing vision loss. Kinases are thus attractive targets for thetreatment of eye diseases involving neovascularization.

Thus, there is a need to develop a strategy for controllingneovascularization of the eye and to develop a strategy for thetreatment of ocular diseases.

Here we describe small molecules that are potent inhibitors of proteintyrosine kinase activity.

BRIEF SUMMARY OF THE INVENTION

The present invention provides new compounds and methods for treating adisease responsive to inhibition of kinase activity, for example adisease responsive to inhibition of protein tyrosine kinse activity, forexample a disease responsive to inhibition of protein tyrosine kinaseactivity of growth factor receptors, for example a disease responsive toinhibition of receptor type tyrosine kinase signaling, or for example, adisease responsive to inhibition of VEGF receptor signaling. In oneembodiment the disease is a cell proliferative disease. In anotherembodiment, the disease is an opthalmological disease. The compounds ofthe invention are inhibitors of kinase activity, such as proteintyrosine kinase activity, for example protein tyrosine kinase activityof growth factor receptors, or for example receptor type tyrosine kinasesignaling.

In a first aspect, the invention provides compounds of Formula (I) thatare useful as kinase inhibitors:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic and scalemic mixtures,diastereomers and enantiomers thereof, wherein D, M, Z, Ar and G are asdefined herein. Because compounds of the present invention are useful askinase inhibitors they are, therefore, useful research tools for thestudy of the role of kinases in both normal and disease states. In someembodiments, the invention provides compounds that are useful asinhibitors of VEGF receptor signaling and, therefore, are usefulresearch tools for the study of of the role of VEGF in both normal anddisease states.

Reference to “a compound of the formula (I)”, (or equivalently, “acompound according to the first aspect”, or “a compound of the presentinvention”, and the like), herein is understood to include reference toN-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic and scalemic mixtures,diastereomers, enantiomers and tautomers thereof, unless otherwiseindicated.

In a second aspect, the invention provides compositions comprising acompound according to the present invention and a pharmaceuticallyacceptable carrier, excipient or diluent. For example, the inventionprovides compositions comprising a compound that is an inhibitor of VEGFreceptor signaling, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, excipient, or diluent.

In a third aspect, the invention provides a method of inhibiting kinaseactivity, for example protein tyrosine kinase, for example tyrosinekinase activity of a growth factor receptor, the method comprisingcontacting the kinase with a compound according to the presentinvention, or with a composition according to the present invention. Insome embodiments of this aspect, the invention provides a method ofinhibiting receptor type tyrosine kinase signaling, for exampleinhibiting VEGF receptor signaling. Inhibition can be in a cell or amulticellular organism. If in a cell, the method according to thisaspect of the invention comprises contacting the cell with a compoundaccording to the present invention, or with a composition according tothe present invention. If in a multicellular organism, the methodaccording to this aspect of the invention comprises administering to theorganism a compound according to the present invention, or a compositionaccording to the present invention. In some embodiments the organism isa mammal, for example a primate, for example a human.

In a fourth aspect, the invention provides a method of inhibitingangiogenesis, the method comprising administering to a patient in needthereof a therapeutically effective amount of a compound according tothe present invention, or a therapeutically effective amount of acomposition according to the present invention. In some embodiments ofthis aspect, the angiogenesis to be inhibited is involved in tumorgrowth. In some other embodiments the angiogenesis to be inhibited isretinal angiogenesis. In some embodiments of this aspect, the patient isa mammal, for example a primate, for example a human.

In a fifth aspect, the invention provides a method of treating a diseaseresponsive to inhibition of kinase activity, for example a diseaseresponsive to inhibition of protein tyrosine kinase activity, forexample a disease responsive to inhibition of protein tyrosine kinaseactivity of growth factor receptors. In some embodiments of this aspect,the invention provides a method of treating a disease responsive toinhibition of receptor type tyrosine kinase signaling, for example adisease responsive to inhibition of VEGF receptor signaling, the methodcomprising administering to an organism in need thereof atherapeutically effective amount of a compound according to the presentinvention, or a composition according to the present invention. In someembodiments of this aspect, the organism is a mammal, for example aprimate, for example a human.

In a sixth aspect, the invention provides a method of treating a cellproliferative disease, the method comprising administering to a patientin need thereof a therapeutically effective amount of a compoundaccording to the present invention, or a therapeutically effectiveamount of a composition according to the present invention. In someembodiments of this aspect, the cell proliferative disease is cancer. Insome embodiments, the patient is a mammal, for example a primate, forexample a human.

In a seventh aspect, the invention provides a method of treating anophthalmic disease, disorder or condition, the method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to the present invention, or atherapeutically effective amount of a composition according to thepresent invention. In some embodiments of this aspect, the disease iscaused by choroidal angiogenesis. In some embodiments of this aspect,the patient is a mammal, for example a primate, for example a human.

In an eighth aspect, the invention provides for the use of a compoundaccording to the present invention for or in the manufacture of amedicament to inhibit kinase activity, for example to inhibit proteintyrosine kinase activity, for example to inhibit protein tyrosine kinaseactivity of growth factor receptors. In some embodiments of this aspect,the invention provides for the use of a compound according to thepresent invention for or in the manufacture of a medicament to inhibitreceptor type tyrosine kinase signaling, for example to inhibit VEGFreceptor signaling. In some embodiments of this aspect, the inventionprovides for the use of a compound according to the present inventionfor or in the manufacture of a medicament to treat a disease responsiveto inhibition of kinase activity. In some embodiments of this aspect,the disease is responsive to inhibition of protein tyrosine kinaseactivity, for example inhibition of protein tyrosine kinase activity ofgrowth factor receptors. In some embodiments of this aspect, the diseaseis responsive to inhibition of receptor type tyrosine kinase signaling,for example VEGF receptor signaling. In some embodiments, the disease isa cell proliferative disease, for example cancer. In some embodiments ofthis aspect, the disease is an ophthalmic disease, disorder orcondition. In some embodiments of this aspect, the ophthalmic disease,disorder or condition is caused by choroidal angiogenesis. In someembodiments of this aspect, the disease is age-related maculardegeneration, diabetic retinopathy or retinal edema.

In a nineth aspect, the invention provides for the use of a compoundaccording to the present invention, or a composition thereof, to inhibitkinase activity, for example to inhibit receptor type tyrosine kinaseactivity, for example to inhibit protein tyrosine kinase activity ofgrowth factor receptors. In some embodiments of this aspect, theinvention provides for the use of a compound according to the presentinvention, or a composition thereof, to inhibit receptor type tyrosinekinase signaling, for example to inhibit VEGF receptor signaling.

In a tenth aspect, the invention provides for the use of a compoundaccording to the present invention, or a composition thereof, to treat adisease responsive to inhibition of kinase activity, for example adisease responsive to inhibition of protein tyrosine kinase activity,for example a disease responsive to inhibition or protein tyrosinekinase activity of growth factor receptors. In some embodiments of thisaspect, the invention provides for the use of a compound according tothe present invention, or a composition thereof, to treat a diseaseresponsive to inhibition of receptor type tyrosine kinase signaling, forexample a disease responsive to inhibition of VEGF receptor signaling.In some embodiments of this aspect, the disease is a cell proliferativedisease, for example cancer. In some embodiments of this aspect, thedisease is an ophthalmic disease, disorder or condition. In someembodiments of this aspect, the ophthalmic disease, disorder orcondition is caused by choroidal angiogenesis.

The foregoing merely summarizes some aspects of the invention and is notintended to be limiting in nature. These aspects and other aspects andembodiments are described more fully below.

DETAILED DESCRIPTION

The invention provides compounds, compositions and methods forinhibiting kinase activity, for example protein tyrosine kinaseactivity, for example receptor protein kinase activity, for example theVEGF receptor KDR. The invention also provides compounds, compositionsand methods for inhibiting angiogenesis, treating a disease responsiveto inhibition of kinase activity, treating cell proliferative diseasesand conditions and treating ophthalmic diseases, disorders andconditions. The patent and scientific literature referred to hereinreflects knowledge that is available to those with skill in the art. Theissued patents, published patent applications, and references that arecited herein are hereby incorporated by reference to the same extent asif each was specifically and individually indicated to be incorporatedby reference. In the case of inconsistencies, the present disclosurewill prevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—.

For simplicity, reference to a “C_(n)-C_(m)”heterocyclyl or“C_(n)-C_(m)”heteroaryl means a heterocyclyl or heteroaryl having from“n” to “m” annular atoms, where “n” and “m” are integers. Thus, forexample, a C₅-C₆heterocyclyl is a 5- or 6-membered ring having at leastone heteroatom, and includes pyrrolidinyl (C₅) and piperazinyl andpiperidinyl (C₆); C₆heteroaryl includes, for example, pyridyl andpyrimidyl.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃ hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” is intended to mean a straight chain or branchedaliphatic group having from 1 to 12 carbon atoms, alternatively 1-8carbon atoms, and alternatively 1-6 carbon atoms. In some embodiments,the alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8carbon atoms and alternatively 2-6 carbon atoms. Examples of alkylgroups include, without limitation, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. A“C₀”alkyl (as in “C₀-C₃alkyl”) is a covalent bond.

The term “alkenyl” is intended to mean an unsaturated straight chain orbranched aliphatic group with one or more carbon-carbon double bonds,having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, andalternatively 2-6 carbon atoms. Examples alkenyl groups include, withoutlimitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” is intended to mean an unsaturated straight chain orbranched aliphatic group with one or more carbon-carbon triple bonds,having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, andalternatively 2-6 carbon atoms. Examples of alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The terms “alkylene,” “alkenylene,” or “alkynylene” as used herein areintended to mean an alkyl, alkenyl, or alkynyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups. Examples of alkylene groups include, withoutlimitation, methylene, ethylene, propylene, and butylene. Examples ofalkenylene groups include, without limitation, ethenylene, propenylene,and butenylene. Examples of alkynylene groups include, withoutlimitation, ethynylene, propynylene, and butynylene.

The term “carbocycle” as employed herein is intended to mean acycloalkyl or aryl moiety.

The term “cycloalkyl” is intended to mean a saturated, partiallyunsaturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbongroup having about 3 to 15 carbons, alternatively having 3 to 12carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, andalternatively 5 or 6 carbons. In some embodiments, the cycloalkyl groupis fused to an aryl, heteroaryl or heterocyclic group. Examples ofcycloalkyl groups include, without limitation, cyclopenten-2-enone,cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl,cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cyclooctyl, etc.

The term “heteroalkyl” is intended to mean a saturated, partiallyunsaturated or unsaturated, straight chain or branched aliphatic group,wherein one or more carbon atoms in the group are independently replacedby a heteroatom selected from the group consisting of O, S, and N.

The term “aryl” is intended to mean a mono-, bi-, tri- or polycyclicaromatic moiety, comprising one to three aromatic rings. In someembodiments the aryl is a C₆-C₁₄aromatic moiety , alternatively the arylgroup is a C₆-C₁₀aryl group, alternatively a C₆ aryl group. Examples ofaryl groups include, without limitation, phenyl, naphthyl, anthracenyl,and fluorenyl.

The terms “aralkyl” or “arylalkyl” are intended to mean a groupcomprising an aryl group covalently linked to an alkyl group. If anaralkyl group is described as “optionally substituted”, it is intendedthat either or both of the aryl and alkyl moieties may independently beoptionally substituted or unsubstituted. In some embodiments, thearalkyl group is (C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation,benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as“arylalkyl” this term, and terms related thereto, is intended toindicate the order of groups in a compound as “aryl-alkyl”. Similarly,“alkyl-aryl” is intended to indicate the order of the groups in acompound as “alkyl-aryl”.

The terms “heterocyclyl”, “heterocyclic” or “heterocycle” are intendedto mean a group which is a mono-, bi-, or polycyclic structure havingfrom about 3 to about 14 atoms, alternatively 3 to 8 atoms,alternatively 4 to 7 atoms, alternatively 5 or 6 atoms wherein one ormore atoms, for example 1 or 2 atoms, are independently selected fromthe group consisting of N, O, and S, the remaining ring-constitutingatoms being carbon atoms. The ring structure may be saturated,unsaturated or partially unsaturated. In some embodiments, theheterocyclic group is non-aromatic, in which case the group is alsoknown as a heterocycloalkyl. In a bicyclic or polycyclic structure, oneor more rings may be aromatic; for example, one ring of a bicyclicheterocycle or one or two rings of a tricyclic heterocycle may bearomatic, as in indan and 9,10-dihydro anthracene. Examples ofheterocyclic groups include, without limitation, epoxy, aziridinyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,thiazolidinyl, oxazolidinyl, oxazolidinonyl, morpholino, thienyl,pyridyl, 1,2,3-triazolyl, imidazolyl, isoxazolyl, pyrazolyl, piperazino,piperidyl, piperidino, morpholinyl, homopiperazinyl, homopiperazino,thiomorpholinyl, thiomorpholino, tetrahydropyrrolyl, and azepanyl. Insome embodiments, the heterocyclic group is fused to an aryl,heteroaryl, or cycloalkyl group. Examples of such fused heterocyclesinclude, without limitation, tetrahydroquinoline and dihydrobenzofuran.Specifically excluded from the scope of this term are compounds where anannular O or S atom is adjacent to another O or S atom.

In some embodiments, the heterocyclic group is a heteroaryl group. Asused herein, the term “heteroaryl” is intended to mean a mono-, bi-,tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6,9, or 10 ring atoms; having for example 6, 10, or 14 pi electrons sharedin a cyclic array; and having, in addition to carbon atoms, between oneor more heteroatoms independently selected from the group consisting ofN, O, and S. For example, a heteroaryl group include, withoutlimitation, pyrimidinyl, pyridinyl, benzimidazolyl, thienyl,benzothiazolyl, benzofuranyl and indolinyl. Other examples of heteroarylgroups include, without limitation, thienyl, benzothienyl, furyl,benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.

The terms “arylene,” “heteroarylene,” or “heterocyclylene” are intendedto mean an aryl, heteroaryl, or heterocyclyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups.

Examples of heterocyclyls and heteroaryls include, but are not limitedto, azepinyl, azetidinyl, acridinyl, azocinyl, benzidolyl,benzimidazolyl, benzofuranyl, benzofurazanyl, benzofuryl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,benzothienyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, benzoxazolyl, benzoxadiazolyl,benzopyranyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, coumarinyl, decahydroquinolinyl, 1,3-dioxolane,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), furanyl, furopyridinyl (such asfuor[2,3-c]pyridinyl, furo[3,2-b]pyridinyl or furo[2,3-b]pyridinyl),furyl, furazanyl, hexahydrodiazepinyl, imidazolidinyl, imidazolinyl,imidazolyl, indazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,isoxazolinyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, oxetanyl, 2-oxoazepinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, pyrrolopyridyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydro-1,1-dioxothienyl, tetrahydrofuranyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl,tetrazolyl, thiazolidinyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl), thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholuiyl sulfone, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, triazinylazepinyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), and xanthenyl.

The term “azolyl” as employed herein is intended to mean a five-memberedsaturated or unsaturated heterocyclic group containing two or morehetero-atoms, as ring atoms, selected from the group consisting ofnitrogen, sulfur and oxygen, wherein at least one of the hetero-atoms isa nitrogen atom. Examples of azolyl groups include, but are not limitedto, optionally substituted imidazolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

As employed herein, and unless stated otherwise, when a moiety (e.g.,alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) isdescribed as “optionally substituted” it is meant that the groupoptionally has from one to four, alternatively from one to three,alternatively one or two, independently selected non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, aralkyl, alkoxy, aryloxy, amino, acylamino,alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl,alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido,aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.

Examples of substituents, which are themselves not further substituted(unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,        guanidino,    -   (b) C₁-C₅alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈alkyl, C₁-C₈alkenyl, C₁-C₈alkoxy,        C₁-C₈alkyamino, C₁-C₈alkoxycarbonyl, aryloxycarbonyl, C₂-C₈acyl,        C₂-C₈acylamino, C₁-C₈alkylthio, arylalkylthio, arylthio,        C₁-C₈alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl,        C₁-C₈alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl,        C₀-C₆N-alkyl carbamoyl, C₂-C₁₅N,N-dialkylcarbamoyl, C₃-C₇        cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to        a cycloalkyl or heterocycle or another aryl ring,        C₃-C₇heterocycle, C₅-C₁₅heteroaryl or any of these rings fused        or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein        each of the foregoing is further optionally substituted with one        more moieties listed in (a), above; and    -   (c) —(CR³²R³³)_(s)—NR³⁰R³¹,        -   wherein s is from 0 (in which case the nitrogen is directly            bonded to the moiety that is substituted) to 6,        -   R³² and R³³ are each independently hydrogen, halo, hydroxyl            or C₁-C₄alkyl, and R³⁰ and R³¹ are each independently            hydrogen, cyano, oxo, hydroxyl, C₁-C₈alkyl,            C₁-C₈heteroalkyl, C₁-C₈alkenyl, carboxamido,            C₁-C₃alkyl-carboxamido, carboxamido-C₁-C₃alkyl, amidino,            C₂-C₈hydroxyalkyl, C₁-C₃alkylaryl, C₁-C₃alkylheteroaryl,            heteroaryl-C₁-C₃alkyl, C₁-C₃alkylheterocyclyl,            heterocyclyl-C₁-C₃alkyl C₁-C₃alkylcycloalkyl,            cycloalkyl-C₁-C₃alkyl, C₂-C₈alkoxy, C₂-C₈alkoxy-C₁-C₄alkyl,            C₁-C₈alkoxycarbonyl, aryloxycarbonyl,            aryl-C₁-C₃alkoxycarbonyl, heteroaryloxycarbonyl,            heteroaryl-C₁-C₃alkoxycarbonyl, C₁-C₈acyl,            C₀-C₈alkyl-carbonyl, aryl-C₀-C₈alkyl-carbonyl,            heteroaryl-C₀-C₈alkyl-carbonyl,            cycloalkyl-C₀-C₈alkyl-carbonyl, C₀-C₈alkyl-NH-carbonyl,            aryl-C₀-C₈alkyl-NH-carbonyl,            heteroaryl-C₀-C₈alkyl-NH-carbonyl,            cycloalkyl-C₀-C₈alkyl-NH-carbonyl, C₀-C₈alkyl-O-carbonyl,            aryl-C₀-C₈alkyl-O-carbonyl,            heteroaryl-C₀-C₈alkyl-O-carbonyl,            cycloalkyl-C₀-C₈alkyl-O-carbonyl, C₁-C₈alkylsulfonyl,            arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl,            heteroarylsulfonyl, C₁-C₈alkyl-NH-sulfonyl,            arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl,            heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl,            aryl, cycloalkyl, heterocyclyl, heteroaryl,            cycloalkyl-C₁-C₃alkyl-, heterocyclyl-C₁-C₃alkyl-,            heteroaryl-C₁-C₃alkyl-, or protecting group, wherein each of            the foregoing is further optionally substituted with one            more moieties listed in (a), above; or        -   R³⁰ and R³¹ taken together with the N to which they are            attached form a heterocyclyl or heteroaryl, each of which is            optionally substituted with from 1 to 3 substituents            selected from the group consisting of (a) above, a            protecting group, and (X³⁰—Y³¹—), wherein said heterocyclyl            may also be bridged (forming a bicyclic moiety with a            methylene, ethylene or propylene bridge); wherein        -   X³⁰ is selected from the group consisting of C₁-C₈alkyl,            C₂-C₈alkenyl-, C₂-C₈alkynyl-,            —C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl,            C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl,            C₀-C₃alkyl-O—C₀-C₃alkyl-, —HO—C₀-C₃alkyl-,            C₀-C₄alkyl-N(R³⁰)—C₀-C₃alkyl-, N(R³⁰)(R³¹)—C₀-C₃alkyl-,            N(R³⁰)(R³¹)—C₀-C₃alkenyl-, N(R³⁰)(R³¹)—C₀-C₃alkynyl-,            (N(R³⁰)(R³¹))₂—C═N—, C₀-C₃alkyl-S(O)₀₋₂—C₀-C₃alkyl-,            CF₃-C₀-C₃alkyl-, C₁-C₈heteroalkyl, aryl, cycloalkyl,            heterocyclyl, heteroaryl, aryl-C₁-C₃alkyl-,            cycloalkyl-C₁-C₃alkyl-, heterocyclyl-C₁-C₃alkyl-,            heteroaryl-C₁-C₃alkyl-,            N(R³⁰)(R³¹)-heterocyclyl-C₁-C₃alkyl-, wherein the aryl,            cycloalkyl, heteroaryl and heterocycyl are optionally            substituted with from 1 to 3 substituents from (a); and        -   Y³¹ is selected from the group consisting of a direct bond,            —O—, —N(R³⁰)—, —C(O)—, —O—C(O)—, —C(O)—O—, —N(R³⁰)—C(O)—,            —C(O)—N(R³⁰)—, —N(R³⁰)—C(S)—, —C(S)—N(R³⁰)—,            —N(R³⁰)—C(O)—N(R³¹)—, N(R³⁰)—C(NR³⁰)—N(R³¹)—,            —N(R³⁰)—C(NR³¹)—, —C(NR³¹)—N(R³⁰)—, —N(R³⁰)—C(S)—N(R³¹)—,            —N(R³⁰)—C(O)—O—, —O—C(O)—N(R³¹)—, —N(R³⁰)—C(S)—O—,            —O—C(S)—N(R³¹)—, —S(O)₀₋₂—, —SO₂N(R³¹)—, —N(R³¹)—SO₂— and            —N(R³⁰)—SO₂N(R³¹)—.

A moiety that is substituted is one in which one or more (for exampleone to four, alternatively from one to three and alternatively one ortwo), hydrogens have been independently replaced with another chemicalsubstituent. As a non-limiting example, substituted phenyls include2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl,2-fluoro-3-propylphenyl. As another non-limiting example, substitutedn-octyls include 2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl.Included within this definition are methylenes (—CH₂—) substituted withoxygen to form carbonyl —CO—.

When there are two optional substituents bonded to adjacent atoms of aring structure, such as for example a phenyl, thiophenyl, or pyridinyl,the substituents, together with the atoms to which they are bonded,optionally form a 5- or 6-membered cycloalkyl or heterocycle having 1,2, or 3 annular heteroatoms.

In some embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and/oraryl group is unsubstituted.

In some embodiments, a hydrocarbyl, heteroalkyl, heterocyclic and/oraryl group is substituted with from 1 to 3 independently selectedsubstituents.

Examples of substituents on alkyl groups include, but are not limitedto, hydroxyl, halogen (e.g., a single halogen substituent or multiplehalo substituents; in the latter case, groups such as CF₃ or an alkylgroup bearing C1₃), oxo, cyano, nitro, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, heterocycle, aryl, —OR^(a), —SR^(a), —S(═O)R^(e),—S(═O)₂R^(e), —P(═O)₂R³, —S(═O)₂OR^(e), —P(═O)₂OR^(e), —NR^(b)R^(c),—NR^(b)S(═O)₂R^(e), —NR^(b)P(═O)₂R^(e), —S(═O)₂NR^(b)R^(c),—P(═O)₂NR^(b)R^(c), —C(═O)OR^(e), —C(═O)R^(a), —C(═O)NR^(b)R^(c),—OC(═O)R^(a), —OC(═O)NR^(b)R^(c), —NR^(b)C(═O)OR^(e),—NR^(d)C(═O)NR^(b)R^(c), —NR^(d)S(═O)₂NR^(b)R^(c),—NR^(d)P(═O)₂NR^(b)R^(c), —NR^(b)C(═O)R^(a) or —NR^(b)P(═O)₂R^(e),wherein R^(a) is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl; R^(b), R^(c) and R^(d) are independentlyhydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R^(b) andR^(c) together with the N to which they are bonded optionally form aheterocycle; and R^(e) is alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl. In the aforementioned exemplarysubstituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkenyl, heterocycle and aryl can themselves be optionallysubstituted.

Examples of substituents on alkenyl and alkynyl groups include, but arenot limited to, alkyl or substituted alkyl, as well as those groupsrecited as examples of alkyl substituents.

Examples of substituents on cycloalkyl groups include, but are notlimited to, nitro, cyano, alkyl or substituted alkyl, as well as thosegroups recited above as examples of alkyl substituents. Other examplesof substituents include, but are not limited to, Spiro-attached or fusedcyclic substituents, for example, spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Examples of substituents on cycloalkenyl groups include, but are notlimited to, nitro, cyano, alkyl or substituted alkyl, as well as thosegroups recited as examples of alkyl substituents. Other examples ofsubstituents include, but are not limited to, spiro-attached or fusedcyclic substituents, for examples spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Examples of substituents on aryl groups include, but are not limited to,nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substitutedcycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groupsrecited above as examples of alkyl substituents. Other examples ofsubstituents include, but are not limited to, fused cyclic groups, suchas fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fusedaryl, where the aforementioned cycloalky, cylcoalkenyl, heterocycle andaryl substituents can themselves be optionally substituted. Still otherexamples of substituents on aryl groups (phenyl, as a non-limitingexample) include, but are not limited to, haloalkyl and those groupsrecited as examples of alkyl substituents.

Examples of substituents on heterocylic groups include, but are notlimited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, nitro, oxo (i.e., ═O), cyano, alkyl,substituted alkyl, as well as those groups recited as examples of alkylsubstituents. Other examples substituents on heterocyclic groupsinclude, but are not limited to, spiro-attached or fused cylicsubstituents at any available point or points of attachment, for examplespiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attachedheterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloakenyl,fused heterocycle and fused aryl, where the aforementioned cycloalkyl,cycloalkenyl, heterocycle and aryl substituents can themselves beoptionally substituted.

In some embodiments, a heterocyclic group is substituted on carbon,nitrogen and/or sulfur at one or more positions. Examples ofsubstituents on nitrogen include, but are not limited to alkyl, aryl,aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl,alkoxycarbonyl, or aralkoxycarbonyl. Examples of substituents on sulfurinclude, but are not limited to, oxo and C₁₋₆alkyl. In some embodiments,nitrogen and sulfur heteroatoms may independently be optionally oxidizedand nitrogen heteroatoms may independently be optionally quaternized.

In some embodiments, substituents on ring groups, such as aryl,heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and/oralkyl.

In some embodiments, substituents on alkyl groups include halogen and/orhydroxy.

A “halohydrocarbyl” as employed herein is a hydrocarbyl moiety, in whichfrom one to all hydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally optionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, dialkylamino (wherein each alkyl may be the same ordifferent), arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from within one of the specified groups or from within thecombination of all of the specified groups.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5- to 6-membered mono- and 9- to14-membered bi-cyclic moieties fused to the parent cyclic moiety to forma bi- or tri-cyclic fused ring system. Substituents on cyclic moietiesalso include 5- to 6-membered mono- and 9- to 14-membered bi-cyclicmoieties attached to the parent cyclic moiety by a covalent bond to forma bi- or tri-cyclic bi-ring system. For example, an optionallysubstituted phenyl includes, but is not limited to, the following:

An “unsubstituted” moiety (e.g., unsubstituted cycloalkyl, unsubstitutedheteroaryl, etc.) means a moiety as defined above that does not have anyoptional substituents.

A saturated, partially unsaturated or unsaturated three- toeight-membered carbocyclic ring is for example a four- toseven-membered, alternatively a five- or six-membered, saturated orunsaturated carbocyclic ring. Examples of saturated or unsaturatedthree- to eight-membered carbocyclic rings include phenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

A saturated or unsaturated carboxylic and heterocyclic group maycondense with another saturated or heterocyclic group to form a bicyclicgroup, for example a saturated or unsaturated nine- to twelve-memberedbicyclic carbocyclic or heterocyclic group. Bicyclic groups includenaphthyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl,indolyl, and 1,2,3,4-tetrahydronaphthyl.

When a carbocyclic or heterocyclic group is substituted by twoC₁₋C₆alkyl groups, the two alkyl groups may combine together to form analkylene chain, for example a C₁₋C₃alkylene chain. Carbocyclic orheterocyclic groups having this crosslinked structure includebicyclo[2.2.2]octanyl and norbornanyl.

The terms “kinase inhibitor” and “inhibitor of kinase activity”, and thelike, are used to identify a compound which is capable of interactingwith a kinase and inhibiting its enzymatic activity.

The term “inhibiting kinase enzymatic activity” is used to mean reducingthe ability of a kinase to transfer a phosphate group from a donormolecule, such as ATP, to a specific target molecule (substrate). Forexample, the inhibition of kinase activity may be at least about 10%. Insome embodiments of the invention, such reduction of kinase activity isat least about 25%, alternatively at least about 50%, alternatively atleast about 75%, and alternatively at least about 90%. In otherembodiments, kinase activity is reduced by at least 95% andalternatively by at least 99%. The IC₅₀ value is the concentration ofkinase inhibitor which reduces the activity of a kinase to 50% of theuninhibited enzyme.

The terms “inhibitor of VEGF receptor signaling” is used to identify acompound having a structure as defined herein, which is capable ofinteracting with a VEGF receptor and inhibiting the activity of the VEGFreceptor. In some embodiments, such reduction of activity is at leastabout 50%, alternatively at least about 75%, and alternatively at leastabout 90%. In some embodiments, activity is reduced by at least 95% andalternatively by at least 99%.

The term “inhibiting effective amount” is meant to denote a dosagesufficient to cause inhibition of kinase activity. The amount of acompound of the invention which constitutes an “inhibiting effectiveamount” will vary depending on the compound, the kinase, and the like.The inhibiting effective amount can be determined routinely by one ofordinary skill in the art. The kinase may be in a cell, which in turnmay be in a multicellular organism. The multicellular organism may be,for example, a plant, a fungus or an animal, for example a mammal andfor example a human. The fungus may be infecting a plant or a mammal,for example a human, and could therefore be located in and/or on theplant or mammal.

In an exemplary embodiment, such inhibition is specific, i.e., thekinase inhibitor reduces the ability of a kinase to transfer a phosphategroup from a donor molecule, such as ATP, to a specific target molecule(substrate) at a concentration that is lower than the concentration ofthe inhibitor that is required to produce another, unrelated biologicaleffect. For example, the concentration of the inhibitor required forkinase inhibitory activity is at least 2-fold lower, alternatively atleast 5-fold lower, alternatively at least 10-fold lower, andalternatively at least 20-fold lower than the concentration required toproduce an unrelated biological effect.

Thus, the invention provides a method for inhibiting kinase enzymaticactivity, comprising contacting the kinase with an inhibitng effectiveamount of a compound or composition according to the invention. In someembodiments, the kinase is in an organism. Thus, the invention providesa method for inhibiting kinase enzymatic activity in an organism,comprising administering to the organism an inhibitng effective amountof a compound or composition according to the invention. In someembodiments, the organism is a mammal, for example a domesticatedmammal. In some embodiments, the organism is a human.

The term “therapeutically effective amount” as employed herein is anamount of a compound of the invention, that when administered to apatient, elicits the desired therapeutic effect. The therapeutic effectis dependent upon the disease being treated and the results desired. Assuch, the therapeutic effect can be treatment of a disease-state.Further, the therapeutic effect can be inhibition of kinase activity.The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the disease state and its severity, the age of the patient to betreated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art.

In some embodiments, the therapeutic effect is inhibition ofangiogenesis. The phrase “inhibition of angiogenesis” is used to denotean ability of a compound according to the present invention to retardthe growth of blood vessels, such as blood vessels contacted with theinhibitor as compared to blood vessels not contacted. In someembodiments, angiogenesis is tumor angiogenesis. The phrase “tumorangiogenesis” is intended to mean the proliferation of blood vesselsthat penetrate into or otherwise contact a cancerous growth, such as atumor. In some embodiments, angiogenesis is abnormal blood vesselformation in the eye.

In an exemplary embodiment, angiogenesis is retarded by at least 25% ascompared to angiogenesis of non-contacted blood vessels, alternativelyat least 50%, alternatively at least 75%, alternatively at least 90%,alternatively at least 95%, and alternatively, at least 99%.Alternatively, angiogenesis is inhibited by 100% (i.e., the bloodvessels do not increase in size or number). In some embodiments, thephrase “inhibition of angiogenesis” includes regression in the number orsize of blood vessels, as compared to non-contacted blood vessels. Thus,a compound according to the invention that inhibits angiogenesis mayinduce blood vessel growth retardation, blood vessel growth arrest, orinduce regression of blood vessel growth.

Thus, the invention provides a method for inhibiting angiogenesis in ananimal, comprising administering to an animal in need of such treatmenta therapeutically effective amount of a compound or composition of theinvention. In some embodiments, the animal is a mammal, for example adomesticated mammal. In some embodiments, the animal is a human.

In some embodiments, the therapeutic effect is treatment of anophthalmic disesase, disorder or condition. The phrase “treatment of anophthalmic disease, disorder or condition” is intended to mean theability of a compound according to the present invention to treat anexudative and/or inflammatory ophthalmic disease, disorder or condition,a disorder related to impaired retinal vessel permeability and/orintegrity, a disorder related to retinal microvessel rupture leading tofocal hemorrhage, a disease of the back of the eye, a retinal disease,or a disease of the front of the eye, or other ophthalmic disease,disorder or condition.

In some embodiments, the ophthalmic disease, disorder or conditionincludes but is not limited to Age Related Macular Degeneration (ARMD),exudative macular degeneration (also known as “wet” or neovascularage-related macular degeneration (wet-AMD), macular oedema, ageddisciform macular degeneration, cystoid macular oedema, palpebraloedema, retinal oedema, diabetic retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, chorioretinopathy,Choroidal Neovascularization, neovascular maculopathy, neovascularglaucoma, obstructive arterial and venous retinopathies (e.g. RetinalVenous Occlusion or Retinal Arterial Occlusion), Central Retinal VeinOcclusion, Disseminated Intravascular Coagulopathy, Branch Retinal VeinOcclusion, Hypertensive Fundus Changes, Ocular Ischemic Syndrome,Retinal Arterial Microaneurysms, Coat's Disease, ParafovealTelangiectasis, Hemi-Retinal Vein Occlusion, Papillophlebitis, CentralRetinal Artery Occlusion, Branch Retinal Artery Occlusion, CarotidArtery Disease(CAD), Frosted Branch Angitis, Sickle Cell Retinopathy andother Hemoglobinopathies, Angioid Streaks, macular oedema occurring as aresult of aetiologies such as disease (e.g. Diabetic Macular Oedema),eye injury or eye surgery, retinal ischemia or degeneration produced forexample by injury, trauma or tumours, uveitis, iritis, retinalvasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia,choroiditis, retinal pigment epithelitis, conjunctivitis, cyclitis,scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis,keratitis, blepharitis, exudative retinal detachment, corneal ulcer,conjunctival ulcer, chronic nummular keratitis, Thygeson keratitis,progressive Mooren's ulcer, an ocular inflammatory disease caused bybacterial or viral infection or by an ophthalmic operation, an ocularinflammatory disease caused by a physical injury to the eye, and asymptom caused by an ocular inflammatory disease including itching,flare, oedema and ulcer, erythema, erythema exsudativum multiforme,erythema nodosum, erythema annulare, scleroedema, dermatitis,angioneurotic oedema, laryngeal oedema, glottic oedema, subglotticlaryngitis, bronchitis, rhinitis, pharyngitis, sinusitis, laryngitis orotitis media.

In some embodiments, the ophthalmic disease, disorder or conditionincludes but is not limited to age-related macular degeneration,diabetic retinopathy, retinal edema, retinal vein occlusion, neovascularglaucoma, retinopathy of prematurity, pigmentary retinal degeneration,uveitis, corneal neovascularization or proliferative vitreoretinopathy.

In some embodiments, the ophthalmic disease, disorder or condition isage-related macular degeneration, diabetic retinopathy or retinal edema.

Thus, the invention provides a method for treating an ophthalmicdisease, disorder or condition in an animal, comprising administering toan animal in need of such treatment a therapeutically effective amountof a compound or composition of the invention. In some embodiments, theanimal is a mammal, for example a domesticated mammal. In someembodiments, the animal is a human.

In some embodiments, the therapeutic effect is inhibition of retinalneovascularization. The phrase “inhibition of retinalneovascularization” is intended to mean the ability of a compoundaccording to the present invention to retard the growth of blood vesselsin the eye, for example new blood vessels originating from retinalveins, for example, to retard the growth of new blood vesselsoriginating from retinal veins and extending along the inner (vitreal)surface of the retina.

In an exemplary embodiment, retinal neovascularization is retarded by atleast 25% as compared to retinal neovascularization of non-contactedblood vessels, alternatively at least 50%, alternatively at least 75%,alternatively at least 90%, alternatively at least 95%, andalternatively, at least 99%. Alternatively, retinal neovascularizationis inhibited by 100% (i.e., the blood vessels do not increase in size ornumber). In some embodiments, the phrase “inhibition of retinalneovascularization” includes regression in the number or size of bloodvessels, as compared to non-contacted blood vessels. Thus, a compoundaccording to the invention that inhibits retinal neovascularization mayinduce blood vessel growth retardation, blood vessel growth arrest, orinduce regression of blood vessel growth.

Thus, the invention provides a method for inhibiting retinalneovascularization in an animal, comprising administering to an animalin need of such treatment a therapeutically effective amount of acompound or composition of the invention. In some embodiments, theanimal is a mammal, for example a domesticated mammal. In someembodiments, the animal is a human.

In some embodiments, the therapeutic effect is inhibition of cellproliferation. The phrase “inhibition of cell proliferation” is used todenote an ability of a compound according to the present invention toretard the growth of cells contacted with the inhibitor as compared tocells not contacted. An assessment of cell proliferation can be made bycounting contacted and non-contacted cells using a Coulter Cell Counter(Coulter, Miami, Fla.) or a hemacytometer. Where the cells are in asolid growth (e.g., a solid tumor or organ), such an assessment of cellproliferation can be made by measuring the growth with calipers orcomparing the size of the growth of contacted cells with non-contactedcells.

In an exemplary embodiment, growth of cells contacted with the inhibitoris retarded by at least 25% as compared to growth of non-contactedcells, alternatively at least 50%, alternatively at least 75%,alternatively at least 90%, alternatively at least 95%, andalternatively, at least 99%. Alternatively, cell proliferation isinhibited by 100% (i.e., the contacted cells do not increase in number).In some embodiments, the phrase “inhibition cell proliferation” includesa reduction in the number or size of contacted cells, as compared tonon-contacted cells. Thus, a compound according to the invention thatinhibits cell proliferation in a contacted cell may induce the contactedcell to undergo growth retardation, to undergo growth arrest, to undergoprogrammed cell death (i.e., to apoptose), or to undergo necrotic celldeath.

In some embodiments, the contacted cell is a neoplastic cell. The term“neoplastic cell” is used to denote a cell that shows aberrant cellgrowth. In some embodiments, the aberrant cell growth of a neoplasticcell is increased cell growth. A neoplastic cell may be a hyperplasticcell, a cell that shows a lack of contact inhibition of growth in vitro,a benign tumor cell that is incapable of metastasis in vivo, or a cancercell that is capable of metastasis in vivo and that may recur afterattempted removal. The term “tumorigenesis” is used to denote theinduction of cell proliferation that leads to the development of aneoplastic growth.

In some embodiments, the contacted cell is in an animal. Thus, theinvention provides a method for treating a cell proliferative disease orcondition in an animal, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orcomposition of the invention. In some embodiments, the animal is amammal, for example a domesticated mammal. In some embodiments, theanimal is a human.

The term “cell proliferative disease or condition” is meant to refer toany condition characterized by aberrant cell growth, such as abnormallyincreased cellular proliferation. Examples of such cell proliferativediseases or conditions amenable to inhibition and treatment include, butare not limited to, cancer. Examples of particular types of cancerinclude, but are not limited to, breat cancer, lung cancer, coloncancer, rectal cancer, bladder cancer, prostate cancer leukemia andrenal cancer. In some embodiments, the invention provides a method forinhibiting neoplastic cell proliferation in an animal comprisingadministering to an animal having at least one neoplastic cell presentin its body a therapeutically effective amount of a compound of theinvention or a composition thereof.

The term “patient” as employed herein for the purposes of the presentinvention includes humans and other animals, for example mammals, andother organisms. Thus the compounds, compositions and methods of thepresent invention are applicable to both human therapy and veterinaryapplications. In some embodiments the patient is a mammal, for example ahuman.

The terms “treating”, “treatment”, or the like, as used herein coversthe treatment of a disease-state in an organism, and includes at leastone of: (i) preventing the disease-state from occurring, in particular,when such animal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (ii) inhibiting the disease-state, i.e.,partially or completely arresting its development; (iii) relieving thedisease-state, i.e., causing regression of symptoms of thedisease-state, or ameliorating a symptom of the disease; and (iv)reversal or regression of the disease-state, such as eliminating orcuring of the disease. In some embodiments of the present invention theorganism is an animal, for example a mammal, for example a primate, forexample a human. As is known in the art, adjustments for systemic versuslocalized delivery, age, body weight, general health, sex, diet, time ofadministration, drug interaction, the severity of the condition, etc.,may be necessary, and will be ascertainable with routine experimentationby one of ordinary skill in the art. In some embodiments, the terms“treating”, “treatment”, or the like, as used herein covers thetreatment of a disease-state in an organism and includes at least one of(ii), (iii) and (iv) above.

Administration for non-opthalmic diseases, disorders or conditions maybe by any route, including, without limitation, parenteral, oral,sublingual, transdermal, topical, intranasal, intratracheal, orintrarectal. In some embodiments, compounds of the invention areadministered intravenously in a hospital setting. In some embodiments,administration may be by the oral route.

Examples of routes of administration for ophthalmic diseases, disordersand conditions include but are not limited to, systemic, periocular,retrobulbar, intracanalicular, intravitral injection, topical (forexample, eye drops), subconjunctival injection, subtenon, transcleral,intracameral, subretinal, electroporation, and sustained-releaseimplant. Other routes of administration other injection sites or otherforms of administration for ophthalmic situations will be known orcontemplated by one skilled in the art and are intended to be within thescope of the present invention.

In some embodiments of the present invention, routes of administrationfor ophthalmic diseases, disorders and conditions include topical,subconjunctival injection, intravitreal injection, or other ocularroutes, systemically, or other methods known to one skilled in the artto a patient following ocular surgery.

In some other embodiments of the present invention, routes ofadministration for ophthalmic diseases, disorders and conditions includetopical, intravitreal, transcleral, periocular, conjunctival, subtenon,intracameral, subretinal, subconjunctival, retrobulbar, orintracanalicular.

In some embodiments of the present invention, routes of administrationfor ophthalmic diseases, disorders and conditions include topicaladministration (for example, eye drops), systemic administration (forexample, oral or intravenous), subconjunctival injection, periocularinjection, intravitreal injection, and surgical implant.

In some embodiments of the present invention, routes of administrationfor ophthalmic diseases, disorders and conditions include intravitrealinjection, periocular injection, and sustained-release implant.

In some embodiments of the present invention, an intraocular injectionmay be into the vitreous (intravitreal), under the conjunctiva(subconjunctival), behind the eye (retrobulbar), into the sclera, underthe Capsule of Tenon (sub-Tenon), or may be in a depot form.

The compounds of the present invention form salts which are also withinthe scope of this invention. Reference to a compound of the invention,for example a compound of Formula (I), herein is understood to includereference to salts thereof, unless otherwise indicated.

The term “salt(s)”, as employed herein, denotes acidic and/or basicsalts formed with inorganic and/or organic acids and bases. In addition,when a compound of the present invention contains both a basic moiety,such as but not limited to a pyridine or imidazole, and an acidic moietysuch as but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic (exhibiting minimalor no undesired toxicological effects), physiologically acceptable)salts are preferred, although other salts are also useful, e.g., inisolation or purification steps which may be employed duringpreparation. Salts of the compounds of the invention may be formed, forexample, by reacting a compound of the present invention with an amountof acid or base, such as an equivalent amount, in a medium such as onein which the salts precipitates or in an aqueous medium followed bylyophilization.

The compounds of the present invention which contain a basic moiety,such as but not limited to an amine or a pyridine or imidazole ring, mayform salts with a variety of organic and inorganic acids. Examples ofacid addition salts include acetates (such as those formed with aceticacid or trihaloacetic acid, for example, trifluoroacetic acid),adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemi sulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfanotes(e.g., 2-hydroxyethanesulfonates), lactates, maleates,methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates, tartrates,thiocyanates, toluenesulfonates such as tosylates, undecanoates, and thelike.

The compounds of the present invention which contain an acidic moiety,such as but not limited to a carboxylic acid, may form salts with avariety of organic and inorganic bases. Examples of basic salts includeammonium salts, alkali metal salts such as sodium, lithium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases (for example, organic amines) such asbenzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibuty and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

As used herein, the term “pharmaceutically acceptable salts” is intendedto mean salts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to, salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, naphthalenedisulfonic acid,methanesulfonic acid, p-toluenesulfonic acid and polygalacturonic acid.Other salts include pharmaceutically acceptable quaternary salts knownby those skilled in the art, which specifically include the quaternaryammonium salt of the formula —NR+Z—, wherein R is hydrogen, alkyl, orbenzyl, and Z is a counterion, including chloride, bromide, iodide,—O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, orcarboxylate (such as benzoate, succinate, acetate, glycolate, maleate,malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

Another aspect of the invention provides compositions comprising acompound according to the present invention. For example, in someembodiments of the invention, a composition comprises a compound,N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex orprodrug of a compound according to the present invention present in atleast about 30% enantiomeric or diastereomeric excess. In someembodiments of the invention, the compound, N-oxide, hydrates, solvate,pharmaceutically acceptable salt, complex or prodrug is present in atleast about 50%, at least about 80%, or even at least about 90%enantiomeric or diastereomeric excess. In some embodiments of theinvention, the compound, N-oxide, hydrate, solvate, pharmaceuticallyacceptable salt, complex or prodrug is present in at least about 95%,alternatively at least about 98% and alternatively at least about 99%enantiomeric or diastereomeric excess. In other embodiments of theinvention, a compound, N-oxide, hydrate, solvate, pharmaceuticallyacceptable salt, complex or prodrug is present as a substantiallyracemic mixture.

Some compounds of the invention may have chiral centers and/or geometricisomeric centers (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, enantiomeric, diastereoisomericand geometric isomers. The invention also comprises all tautomeric formsof the compounds disclosed herein. Where compounds of the inventioninclude chiral centers, the invention encompasses the enantiomericallyand/or diasteromerically pure isomers of such compounds, theenantiomerically and/or diastereomerically enriched mixtures of suchcompounds, and the racemic and scalemic mixtures of such compounds. Forexample, a composition may include a mixture of enantiomers ordiastereomers of a compound of Formula (1) in at least about 30%diastereomeric or enantiomeric excess. In some embodiments of theinvention, the compound is present in at least about 50% enantiomeric ordiastereomeric excess, in at least about 80% enantiomeric ordiastereomeric excess, or even in at least about 90% enantiomeric ordiastereomeric excess. In some embodiments of the invention, thecompound is present in at least about 95%, alternatively in at leastabout 98% enantiomeric or diastereomeric excess, and alternatively in atleast about 99% enantiomeric or diastereomeric excess.

The chiral centers of the present invention may have the S or Rconfiguration. The racemic forms can be resolved by physical methods,such as, for example, fractional crystallization, separation orcrystallization of diastereomeric derivates or separation by chiralcolumn chromatography. The individual optical isomers can be obtainedeither starting from chiral precursors/intermediates or from theracemates by any suitable method, including without limitation,conventional methods, such as, for example, salt formation with anoptically active acid followed by crystallization.

The present invention also includes prodrugs of compounds of theinvention. The term “prodrug” is intended to represent a compoundcovalently bonded to a carrier, which prodrug is capable of releasingthe active ingredient when the prodrug is administered to a mammaliansubject. Release of the active ingredient occurs in vivo. Prodrugs canbe prepared by techniques known to one skilled in the art. Thesetechniques generally modify appropriate functional groups in a givencompound. These modified functional groups however regenerate originalfunctional groups by routine manipulation or in vivo. Prodrugs ofcompounds of the invention include compounds wherein a hydroxy, amino,carboxylic, or a similar group is modified. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) ofhydroxy or amino functional groups in compounds of the presentinvention), amides (e.g., trifluoroacetylamino, acetylamino, and thelike), and the like.

The compounds of the invention may be administered, for example, as isor as a prodrug, for example in the form of an in vivo hydrolyzableester or in vivo hydrolyzable amide. An in vivo hydrolyzable ester of acompound of the invention containing carboxy or hydroxy group is, forexample, a pharmaceutically acceptable ester which is hydrolyzed in thehuman or animal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁-C₆alkoxymethylesters (e.g., methoxymethyl), C₁-C₆alkanoyloxymethyl esters (e.g., forexample pivaloyloxymethyl), phthalidyl esters,C₃-C₈cycloalkoxycarbonyloxy-C₁-C₆alkyl esters (e.g.,1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g.,5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆alkoxycarbonyloxyethylesters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at anyappropriate carboxy group in the compounds of this invention.

An in vivo hydrolyzable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters anda-acyloxyalkyl ethers and related compounds which as a result of the invivo hydrolysis of the ester breakdown to give the parent hydroxy group.Examples of α-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),N,N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.A suitable value for an in vivo hydrolyzable amide of a compound of theinvention containing a carboxy group is, for example, a N—C₁-C₆alkyl orN,N-di-C₁-C₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Upon administration to a subject, the prodrug undergoes chemicalconversion by metabolic or chemical processes to yield a compound of thepresent invention, for example, a salt and/or solvate thereof. Solvatesof the compounds of the present invention include, for example,hydrates.

Throughout the specification, embodiments of one or more chemicalsubstituents are identified. Also encompassed are combinations ofvarious embodiments. For example, the invention describes someembodiments of D in the compounds and describes some embodiments ofgroup G. Thus, as an example, also contemplated as within the scope ofthe invention are compounds in which examples of D are as described andin which examples of group G are as described.

Compounds

According to one embodiment, the invention provides compounds of Formula(I):

including N-oxides, hydrates, solvates, pharmaceutically acceptablesalts, prodrugs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof, wherein,

-   D is selected from the group consisting of an aromatic,    heteroaromatic, cycloalkyl or heterocyclic ring system, each of    which is optionally substituted with 1 to 5 independently selected    R³⁸;-   M is an optionally substituted fused heterocyclic moiety;-   Z is —O—;-   Ar is a 5 to 7 membered aromatic ring system, which is optionally    substituted with 0 to 4 R² groups; and-   G is a group B-L-T, wherein    -   B is —N(R¹³)— or —C(═S)—;    -   L is selected from the group consisting of —C(═O)N(R¹³)—,        —C(═O)C₀₋C₁alkyl-C(═O)N(R¹³)—, and —C(═O)—, wherein an alkyl        group of the aforementioned L group is optionally substituted;        and    -   T is selected from the group consisting of —C₀₋C₅alkyl,        —C₀₋C₅alkyl-Q, —O—C₀₋C₅alkyl-Q, —O—C₀₋C₅alkyl,        —C(═S)≧N(R¹³)—C₀₋C₅alkyl-Q, —C₀₋C₅alkyl-S(O)₂-Q, and        —C(═S)—N(R¹³)—C₀₋C₅alkyl, wherein each C₀₋C₅alkyl is optionally        substituted;        wherein-   each R³⁸ is independently selected from the group consisting of    halo, optionally substituted C₁-C₆ alkyl, —C₀-C₆alkyl-(optionally    substituted heterocycle), optionally substituted    —C₂-C₆alkenyl=N-heterocycle-C₁-C₆alkyl, optionally substituted    —CH═N-heterocycle, —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,    —(CH₂)_(j)NR³⁹C(O)(CH₂)O(CH₂)_(j)OR³,    —(CH₂)_(j)NR³⁹(CH₂)_(j)(CH)(NH₂)(COOH) and    —(CH₂)_(j)NR³⁹(CH₂)_(j)COOH;    wherein-   each j is an integer independently ranging from 0 to 4,    alternatively 1-2,-   n is an integer ranging from 0 to 6,-   x is an integer ranging from 0-6, alternatively 2-3,-   each i is independently 2 or 3, and-   the —(CH₂)_(n)— moieties of the foregoing R³⁸ groups are optionally    substituted with C₁-C₆ alkyl;-   R³⁶ is H or —(CH₂)_(n3)OR³⁷;    wherein-   n3 is an integer ranging from 0 to 6;-   with the proviso that when R³⁶ and R³⁹ are both attached to the same    nitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogen    directly through an oxygen;-   each R³⁷ is independently selected from H, C₁-C₆ alkyl,    —(CH₂)_(n)O(CH₂)_(a)O—C₁-C₆alkyl,    —(CH₂)_(n)CH(NH)(CH₂)—O—C₁-C₆alkyl,    —(CH₂)_(n)CH(NH)(CH₂)_(n)C₁-C₆alkyl,    —(CH₂)_(n)O(CH₂)_(a)O—C₃-C₁₀cycloalkyl,    —(CH₂)_(n)CH(NH)(CH₂)_(n)O—C₃-C₁₀cycloalkyl and    —(CH₂)_(n)CH(NH)(CH₂)_(n)C₃-C₁₀cycloalkyl, wherein each n is an    integer independently ranging from 0 to 6 and a is an integer    ranging from 2 to 6, wherein the alkyl and cycloalkyl moieties of    the foregoing R³⁷ groups are optionally substituted by one or more    independently selected substituents;-   R³⁹ is selected from the group consisting of H, C₁-C₆ alkyl,    —SO₂—C₁-C₆alkyl, —C(O)—C₁-C₆ alkyl, —C(O)O—C₁-C₆alkyl,    —C(O)—C₁-C₆alkyl-NR³R³, —C₁-C₆alkyl-O—C₁-C₆alkyl,    —C(O)(CH₂)₀₋₄O(CH₂)₁₋₄OC₁-C₆alkyl, —C(O)—C₁-C₆alkyl-OH and    —C(O)CH[CH(C₁-C₆alkyl)₂]NR³R³ and a protecting group used to protect    secondary amino groups with the proviso that when R³⁶ and R³⁹ are    both attached to the same nitrogen, then R³⁶ and R³⁹ are not both    bonded to the nitrogen directly through an oxygen;-   R⁹⁹ at each occurrence is independently —H, —NH₂ or —OR³;-   R² at each occurrence is independently selected from —H and halogen;-   each R³ is independently selected from the group consisting of —H    and R⁴;-   R⁴ is (C₁-C₆)alkyl;-   each R¹³ is independently selected from the group consisting of —H,    —C(O)NR³R³ and C₁-C₆ alkyl;-   Q is a three- to ten-membered ring system, optionally substituted    with between zero and four of R²⁰; and-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —OR³, —S(O)₀₋₂R³, —S(O)₂NR³R³, —C(O)OR³,    —C(O)NR³R³, —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl,    —(CH₂)_(n)P(═O)(C₁-C₆alkyl)₂, wherein n is an integer ranging from 0    to 6, and the heteroaryl and C₁-C₆ alkyl are optionally substituted.

In some embodiments of the compounds according to the present inventionD is an aromatic or heteroaromatic ring system, each of which issubstituted with 1 or 2 independently selected R³⁸ groups.

In some embodiments according to the present invention, D is a 5- or6-membered heteroaromatic ring system, each of which is substituted with1 or 2 independently selected R³⁸ groups.

In some embodiments according to the present invention, D is a6-membered aromatic or 6-membered heteroaromatic ring system, each ofwhich is substituted with 1 or 2 independently selected R³⁸ groups.

In some embodiments according to the present invention, D is a6-membered aromatic ring system, substituted with 1 or 2 independentlyselected R³⁸ groups.

In some embodiments according to the present invention, D is a6-membered heteroaromatic ring system, substituted with 1 or 2independently selected R³⁸ groups.

In some embodiments according to the present invention, D is a5-membered heteroaromatic ring system, substituted with 1 or 2independently selected R³⁸ groups.

In some embodiments of the present invention, D is selected from thegroup consisting of

wherein the members of said group are substituted with 1 or 2independently selected R³⁸ groups.

In some embodiments of the present invention, D is selected from thegroup consisting of

wherein the members of said group are substituted with 1 or 2independently selected R³⁸ groups.

In some embodiments according to the present invention, D is substitutedwith one R³⁸ group.

In some embodiments of the present invention, D is phenyl, pyridyl,imidazolyl or tetrahydropyridyl, each of which is substituted with 1 or2 independently selected R³⁸ groups.

In some embodiments according to the present invention, R³⁸ is

In some embodiments according to the present invention, D is phenyl,substituted with 1 R³⁸ groups.

In some embodiments according to the present invention, D is pyridyl,substituted with 1 or 2 independently selected R³⁸ groups.

In some embodiments according to the present invention, D is pyridyl,substituted with one R³⁸.

In some embodiments according to the present invention, D is imidazolyl,substituted with one or two R³⁸.

In some embodiments according to the present invention, D is imidazolyl,substituted with two R³⁸.

In some embodiments of the present invention, D is tetrahydropyridylsubstituted with 1 R³⁸ group.

In some embodiments of the present invention, each R³⁸ is independentlyselected from the group consisting of C₁-C₆ alkyl,—(CH₂)_(j)NR³⁹(CH₂)_(i)[(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶ and —C₀-C₆alkyl-(optionally substitutedheterocycle).

In some embodiments of the present invention each R³⁸ is independentlyselected from the group consisting of C₁-C₆ alkyl,—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, and—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In some embodiments of the present invention, each R³⁸ is independently—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹ or—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In some embodiments of the present invention, R³⁸ is—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is 1 and n is 2.

In some embodiments of the present invention R³⁸ is—(CH₂)NR³⁹(CH₂)₂OCH₃.

In some embodiments of the present invention, R³⁸ is—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH_(i))]_(x)(CH₂)_(j)R⁹⁹.

In some embodiments of the present invention, R³⁸ is—(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹, wherein j is 1, iis 2, and x is 3 or 3.

In some embodiments of the present invention, D is pyridyl subsitutedwith one —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, alternatively one—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, wherein j is 1 and n is 2.

In some embodiments of the present invention, D is pyridyl substitutedwith one —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,alternatively one —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)OMe,wherein j is 1, i is 2, and x is 2 or 3.

In some embodiments of the present invention, D is pyridyl substitutedwith one —(CH₂)_(j)NR³⁹(CH₂)_(j)(CH)(NH₂)(COOH).

In some embodiments of the present invention, D is pyridyl substitutedby one —C₀-C₆alkyl-(optionally substituted heterocycle), for example—C₀-C₆alkyl-(heterocycle substituted with one oxo).

In some embodiments of the present invention, D is pyridyl subsittutedwith one —(CH₂)_(j)NR³⁹(CH₂)_(j)COOH.

In some embodiments of the present invention, D is pyridyl substitutedwith one —(CH₂)_(j)NR³⁹C(O)(CH₂)_(j)O(CH₂)_(j)OR³.

In some embodiments of the present invention D is tetrahydropyridylsubstituted with one optionally substituted —CH═N-heterocycle.

In some embodiments of the present invention D is tetrahydropyridylsubstituted with one —C(O)(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In some embodiments of the present invention D is imidazolyl subsitutedwith one C₁-C₆alkyl and one —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶.

In some embodiments of the present invention, D is phenyl substitutedwith one —(CH)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹.

In some embodiments of the present invention, R³⁹ is selected from thegroup consisting of H, —C(O)—C₁-C₆ alkyl (for example, —C(O)-Me),—C(O)—C₁-C₆alkyl-NH₂, —SO₂-Me, —C(O)(CH₂)₀₋₄O(CH₂)₁₋₄OC₁-C₆alkyl and—C(O)CH[CH(C₁-C₆alkyl)₂]NR³R³.

In another embodiment of the present invention, R³⁹ is selected from thegroup consisting of H, —C(O)-Me, —C(O)(CH₂)O(CH₂)₂OC₁alkyl and—C(O)CH(CHMe₂)NH₂.

In some embodiments of the present invention, R³⁹ is H or —C(O)-Me.

In some embodiments of the present invention, R³⁹ is H.

In some embodiments of the present invention R³⁶ is —OMe.

In some embodiments of the present invention, R⁹⁹ is —OMe.

In some embodiments of the present invention, M is

wherein

-   * represents the point of attachment to D; and-   † represents the point of attachment to Z.

In some embodiments of the present invention, Ar is selected from thegroup consisting of phenyl, pyrazine, pyridazine, pryimidine andpyridine, wherein each of said phenyl, pyrazine, pyridazine, pryimidineand pyridine is optionally substituted with 0 to 4 R² groups.

In some embodiments of the present invention, Ar is phenyl, optionallysubstituted with 0 to 4 R² groups, alternatively with 1 or 2 R² groups,alternatively with 0, 1 or 2 halo.

In some embodiments of the present invention, Ar is phenyl substitutedwith one halo, for example one F.

In some embodiments of the present invention, G is selected from thegroup consisting of

In some embodiments of the present invention, G is selected from thegroup consisting of

In some embodiments of the present invention, G is selected from thegroup consisting of

In some embodiments of the present invention, Q is selected from thegroup consisting of phenyl, cyclopropyl, isoxazolyl, cyclohexyl,thiazolyl, tetrahydrofuran, pyrazolyl, cyclobutyl and cyclopentyl,optionally substituted with between zero and two R²⁰.

In some embodiments of the present invention, Q is phenyl, optionallysubstituted with one or two R²⁰.

In some embodiments of the presention invention, Q is cyclopropyl.

In some embodiments of the presention invention Q is tetrahydrofuran.

In some embodiments of the present invention, Q is pyrazolyl optionallysubstituted with one R²⁰.

In some embodiments of the present invention, each R²⁰ is independentlyselected from the group consisting of —P(═O)(Me)₂, methyl, halo (forexample F), trihalomethyl, methoxy, —C(O)NH₂, heteroaryl, —COON,—SO₂HN₂, —C(O)NH₂, —COOMe, —C(O)N(H)(Me), —C(O)N(Me)₂ and —SO₂Me.

In some embodiments of the present invention, Q is substituted with oneR²⁰ selected from —P(═O)(Me)₂, methyl and methoxy.

In some embodiments of the present invention, Q is phenyl substitutedwith one —P(═O)(Me)₂.

In some embodiments of the present invention, Q is pyrazolyl, isoxazolylor thiazolyl substituted with one methyl.

In some embodiments of the present invention,

-   D is phenyl, pyridyl, imidazolyl or tetrahydropyridyl, each of which    is substituted with 1 or 2 independently selected R³⁸ groups;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example with between zero and four halo; and-   G is selected from the group consisting of

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In some embodiments of the present invention,

-   D is pyridyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,    —C₀-C₆alkyl-(heterocycle optionally substituted with one or two    oxo), —(CH₂)_(j)NR³⁹(CH₂)_(j)COOH or    —(CH₂)_(j)NR³⁹(CH₂)_(j)(CH)(NH₂)(COOH);-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example one F; and-   G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In some embodiments of the present invention,

-   D is pyridyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,    —C₀-C₆alkyl-(heterocycle substituted with one oxo),    —(CH₂)_(j)NR³⁹(CH₂)_(j)COOH or    —(CH₂)_(j)NR³⁹(CH₂)_(j)(CH)(NH₂)(COOH);-   R⁹⁹ is OMe;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is phenyl optionally substituted with 1 or 2 independently    selected R²⁰, wherein each R²⁰ is independently selected from the    group consisting of —P(═O)(Me)₂, methyl, halo (for example F),    trihalomethyl, methoxy, —C(O)NH₂, heteroaryl, —COON, —SO₂HN₂,    —C(O)NH₂, —COOMe, —C(O)N(H)(Me), —C(O)N(Me)₂ and —SO₂Me, or Q is    pyrazolyl optionally substituted with methyl, or Q is cyclopropyl,    cyclobutyl or tetrahydrofuran.

In some embodiments of the present invention,

-   D is pyridyl substituted with —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,    —(CH₂)_(j)NR³⁹(CH₂)_(i)[O(CH ₂)_(i)]_(x)(CH₂)_(j)R⁹⁹,    —C₀-C₆alkyl-(heterocycle substituted with one oxo),    —(CH₂)_(j)NR³⁹(CH₂)_(j)COOH or    —(CH₂)_(j)NR³⁹(CH₂)_(j)(CH)(NH₂)(COOH);-   R⁹⁹ is OMe;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is cyclopropyl.

In some embodiments of the present invention,

-   D is pyridyl substituted with —C₀-C₆alkyl-(optionally substituted    heterocycle);-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is cyclopropyl.

In some embodiments of the present invention,

-   D is pyridyl substituted with —C₀-C₆alkyl-(heterocycle optionally    substituted with one or two oxo), for example —CH₂-(5- or 6-membered    heterocyclyl substituted with 0, 1 or 2 oxo);

M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is cyclopropyl.

In some embodiments of the present invention,

-   D is pyridyl substituted with

-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is cyclopropyl.

In some embodiments of the present invention,

-   D is pyridyl substituted with    —(CH₂)_(i)NR³⁹(CH₂)_(i)[O(CH₂)_(i)]_(x)(CH₂)_(j)R⁹⁹;-   R⁹⁹ is OMe;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is cyclopropyl.

In some embodiments of the present invention,

-   D is imidazolyl subsituted with one C₁-C₆alkyl and one    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example one F; and-   G is

wherein Q is optionally substituted with from 0 to 4 independentlyselected R²⁰.

In some embodiments of the present invention,

-   D is imidazolyl subsituted with one C₁-C₆alkyl and one    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted one F; and-   G is

wherein

-   R¹³ is H; and-   Q is phenyl optionally substituted with from 0 to 4 independently    selected R²⁰.

In some embodiments of the present invention,

-   D is imidazolyl subsituted with one C₁-C₆alkyl and one    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶;-   M is

-   Z is —O—;-   Ar is phenyl optionally substituted with 0 to 4 R² groups, for    example phenyl substituted with one F; and-   G is

wherein

-   R¹³ is H; and-   Q is phenyl optionally substituted with one or two groups    independently selected from the group consisting of —P(O)Me₂,    methyl, halo (for example F), trihalomethyl (for example    trifluoromethyl), methoxy, —C(O)NH₂ and heteroaryl (for example    oxazolyl), or Q is cyclopropyl.

Compounds of above formulas may generally be prepared according to thefollowing Schemes. Tautomers and solvates (e.g., hydrates) of thecompounds of above formulas are also within the scope of the presentinvention. Methods of solvation are generally known in the art.Accordingly, the compounds of the present invention may be in the free,hydrate or salt form, and may be obtained by methods exemplified by thefollowing schemes below.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

Compounds according to the invention include but are not limited tothose described in the examples below. Compounds were named usingChemdraw Ultra version 10.0 or version 8.0.3, which are availablethrough Cambridgesoft.com, 100 Cambridge Park Drive, Cambridge, Mass.02140, or were derived therefrom.

The data presented herein demonstrate the inhibitory effects of thekinase inhibitors of the invention. These data lead one to reasonablyexpect that the compounds of the invention are useful not only forinhibition of kinase activity, protein tyrosine kinase activity, orembodiments thereof, such as, VEGF receptor signaling, but also astherapeutic agents for the treatment of proliferative diseases,including cancer and tumor growth and opthalmological diseases,disorders and conditions.

Synthetic Schemes and Experimental Procedures

The compounds of the invention can be prepared according to the reactionschemes or the examples illustrated below utilizing methods known to oneof ordinary skill in the art. These schemes serve to exemplify someprocedures that can be used to make the compounds of the invention. Oneskilled in the art will recognize that other general syntheticprocedures may be used. The compounds of the invention can be preparedfrom starting components that are commercially available. Any kind ofsubstitutions can be made to the starting components to obtain thecompounds of the invention according to procedures that are well knownto those skilled in the art.

PARTICULAR EXAMPLES

tert-Butyl(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(46) Step 1. 5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazole (38) [Shaflee A.,Rastkary N., Jorjani M., Shafaghi B., Arch. Pharm. Pharm. Med. Chem.2002, 2, 69-76]

To a solution of 1-methyl-1H-imidazole-5-carbaldehyde (2.9 g, 26.3 mmol)in toluene (20 mL) was added propane-1,3-diol (4.01 g, 52.7 mmol) andCSA (0.306 g, 1.317 mmol) and the reaction mixture was heated to refluxwith azeotropic removal of the evolved water for 24 hours. The reactionmixture was cooled to RT, diluted with DCM and washed with NaHCO3solution. It was then dried over Na2SO4, filtered and concentrated.Purification by column chromatography (80% EtOAc in Hexane to EtOAc)afforded 38 (2.53 g, 57% yield) as a yellow oil which solidified onstanding to a yellow solid. MS (m/z): 169.2 (M+H).

Step 2. 5-(1,3-Dioxan-2-yl)-2-iodo-1-methyl-1H-imidazole (39)

To a solution of 38 (295 g, 1.754 mmol) in dry THF (10 mL) at −78° C.was added n-BuLi (0.772 mL, 1.929 mmol, 2.5 M solution in hexanes) andthe reaction mixture was stirred for 20 min. Iodine (445 mg, 1.754 mmol)in THF (2 mL) was slowly added dropwise while maintaining thetemperature at −78° C. and the reaction mixture was stirred for afurther 30 min, and was quenched by the addition of water and thenextracted with EtOAc. The organic phase was, washed with sodiumthiosulfate solution, separated, dried over Na₂SO₄, filtered andconcentrated. Purification by column chromatography (20% EtOAc/Hexane)afforded 39 (305 mg, 59% yield) as a white solid. MS (m/z): 294.1 (M+H).

Step 3.2-(5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazol-2-yl)-7-chlorothieno[3,2-b]pyridine(40)

To a solution of 7-chlorothieno[3,2-b]pyridine (1) [Klemm, L. H.;Louris, J. N.; Boisvert, W.; Higgins, C.; Muchiri, D. R.; J.Heterocyclic Chem., 22, 1985, 1249-1252] (11.7 g, 69.0 mmol) in THF (300mL) was added, at −78° C., a solution of n-BuLi (30.46 mL, 76 mmol, 2.5M in hexanes) and the reaction mixture was stirred for 10 min. Asolution of ZnCl₂ (76.15 mL, 76 mmol, 1.0 M in Et₂O) was added and themixture was stirred at RT for 10 min. Pd(PPh₃)₄ (2.287 mg, 0.104 mmol)was added along with a solution of 39 (5.82 g, 19.79 mmol) in THF (20mL) and the reaction mixture was heated to reflux under an atmosphere ofN₂ gas for 4 hours. The reaction was then cooled to RT, and diluted withammonium hydroxide and EtOAc. The organic phase was collected, driedover Na₂SO₄, filtered and concentrated. The resultant material wastriturated with Et₂O to afford the title compound 40 (5.79 g, 87% yield)as a white solid. MS (m/z): 336.1 (M+H).

Step 4.2-(5-(1,3-Dioxan-2-yl)-1-methyl-1H-imidazol-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine,(41)

A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g,35.1 mmol) and NaHCO₃ (1.346 g, 16.02 mmol) in Ph₂O (7 mL) was heated to180° C. for 4 hours. The reaction mixture was cooled to RT and dilutedwith DCM, filtered and concentrated. Purification of the residue bycolumn chromatography (eluent EtOAc) afforded 41 (2.5 g, 31% yield) as ayellow solid. MS (m/z): 457.1 (M+H).

Step 5.2-(5-(Dimethoxymethyl)-1-methyl-1H-imidazol-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(42)

To a solution of 41 (2.5 g, 5.48 mmol) in MeOH (200 mL) was added CSA(127 mg, 0.548 mmol) and the reaction mixture was heated to reflux for 5hours. It was then cooled to RT and solid NaHCO₃ was added. The mixturewas filtered and the filtrate was concentrated to dryness. The residualsolid was dissolved in DCM, washed with water, dried over Na₂SO₄,filtered and concentrated. The resultant solid was triturated with Et₂Oto afford 42 (1.8 g, 74% yield) which was used without any furtherpurification. MS (m/z): 445.1 (M+H).

Step 6.2-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carbaldehyde(43)

To a solution 42 (1.8 g, 4.05 mmol) in acetone (100 mL) and water (100mL) was added diluted HCl (20 mL, 2M, 40.0 mmol) and the reactionmixture was stirred at RT overnight. It was then concentrated todryness. The residual solid was dissolved in DCM, washed with water,dried over Na₂SO₄, filtered and concentrated. The resultant solid wastriturated with Et₂O to afford 43 (1.3 g, 81% yield), which used withoutadditional purification. MS (m/z): 399.2 (M+H).

Step 7.N-((2-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)-2-methoxyethanamine(44)

To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 mL) at RT wasadded 2-methoxyethanamine (1.226 g, 16.32 mmol), acetic acid (0.98 g,16.32 mmol) and sodium triacetoxyborohydride (3.46 g, 16.32 mmol), andthe reaction mixture was stirred at RT for 24 hours. It was then dilutedwith additional DCM and washed with saturated NaHCO₃ solution, driedover Na₂SO₄, filtered and concentrated to dryness to afford 44 (1.5 g,100% yield) as an yellow oil which was used crude in the next step withno additional purification. MS (m/z): 458.2 (M+H).

Step 8.tent-Butyl(2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(45)

To a solution of 44 (1.5 g, 3.28 mmol) in DCM (50 mL) at RT was addedBoc₂O (1.073 mg, 4.92 mmol) and the reaction mixture was stirred at RTovernight. The mixture was concentrated to dryness and the residue waspurified by column chromatography (eluent EtOAc) to afford 45 (1.3 g,71% yield) as a yellow solid. MS (m/z): 558.2 (M+H).

Step 9.tert-Butyl(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(46)

To a solution of 45 (1.1 g, 0.717 mmol) in MeOH (30 mL) and water (10mL) was added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g,17.76 mmol) and the reaction mixture was heated to reflux for 24 hours.The reaction mixture was cooled to RT then concentrated to dryness. Theresidue was partitioned between DCM and water and the organic phase wascollected, dried over Na₂SO₄, filtered and concentrated to afford thetitle compound 46 (1.04 g, 100% yield), which was used crude in the nextstep with no additional purification. MS (m/z): 528.1 (M+H).

tert-Butyl(6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(126) Step 1. N-((6-Bromopyridin-3-yl)methyl)-2-methoxyethanamine (143)

To a solution of 6-bromopyridine-3-carbaldehyde (5 g, 26.9 mmol) in DCM(40 mL). was added 2-methoxyethylamine (2.80 mL, 32.3 mmol). After 10min, sodium triacetoxyborohydride (7.98 g, 37.6 mmol) was added to themixture and it was stirred at r.t for 17 h. DCM (100 mL water (50 mL andNH₄Cl (50 mL) were added to the reaction mixture. The organic phase wascollected and the aqueous layer was extracted with DCM (3×100 mL). Thecombined organic solutions were washed with brine and concentrated underreduce pressure. The residue was purified by flash columnchromatography, eluent 98/2 to 95/5 DCM/MeOH, to afford title 143 (2.958g, 45% yield) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.31(dd, J=2.6, 0.6 Hz, 1H), 7.70 (dd, J=8.2, 2.6 Hz, 1H), 7.58 (d, J=8.4Hz, 1H), 3.69 (s, 2H), 3.37 (t, J=5.8 Hz, 2H), 3.22 (s, 3H), 2.60 (t,J=5.8 Hz, 2H). MS (m/z): 245.1 (M+H).

Step 2. tert-Butyl(6-bromopyridin-3-yl)methyl(2-methoxyethyl) carbamate(144)

To a solution of 143 (13.072 g, 53.3 mmol) in THF (40 mL) was addeddi-tert-butyl dicarbonate (14.86 mL, 64.0 mmol). The mixture was stirredat r.t. for 16 h and concentrated under reduce pressure. The residue waspurified by flash column chromatography, eluent Hexane/EtOAc: 7/3, 6/4,5/5, to afford title compound 144 (16.196 g, 88% yield) as a yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.26 (dd, J=2.4, 0.8 Hz, 1H),7.64-7.58 (m, 2H), 4.39 (s, 2H), 3.40-3.33 (m, 4H), 3.20 (s, 3H),1.41-1.31 (m, 9H). MS (m/z): 345.2 (M+H).

Step 3.tert-Butyl(6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(145)

To a solution of 7-chlorothieno[3,2-b]pyridine (1) (8.84 g, 52.1 mmol)in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether)was added at −78° C. and the reaction mixture was warmed to r.t. After 1h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and 144 (6g, 17.38 mmol) in THF (25 mL) were added and the mixture was heated toreflux for 1 h. It was then partitioned between saturated aqueous NaHCO₃solution and EtOAc. The organic layer was collected and the aqueouslayer was extracted with EtOAc (3×100mL). The combined organic layerswere washed with brine and evaporated under reduce pressure. The residuewas purified by flash column chromatography, eluents Hexane/EtOAc: 5/5,3/7, 0/10, to afford compound 145 (5.41 g, 72% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39(s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d,J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33(m, 9H). MS (m/z): 434.2 (M+H).

Step 4.tert-Butyl(6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(126)

To a solution of 4-amino-2-fluorophenol (1.933 g, 15.21 mmol) in DMSO(30 mL) was added potassium tert-butoxide (2.017 g, 17.97 mmol). After30 min, chloride 145 (6 g, 13.83 mmol) was added and the reactionmixture was heated at 100° C. for 45 min. The mixture was cooled downthen poured in water (250 mL) at 40-45° C. and stirred for 30 min. Theprecipitate was collected by filtration, washed with water (2×30 mL) anddried overnight. The crude solid was triturated with Et₂O (50 mL) for 1h, to afford title compound 126 (4.18 g, 58% yield) as a brown solid. MS(m/z): 525.2 (M+H).

Example 1791-(3-(Dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(289) Step 1. 1-(dimethylphosphoryl)-3-nitrobenzene (286)

To a solution of 1-iodo-3-nitrobenzene (2.4 g, 9.6 mmol) in dry1,4-dioxane (24 ml) in a pressure bottle under nitrogen at roomtemperature was added dimethylphosphine oxide [WO 2005/009348] (1.5 g,19.2 mmol), Pd₂(dba)₃ (0.44 g, 0.48 mmol), Xantphos (0.56 g, 0.96 mmol)and cesium cabonate (4.38 g, 13.5 mmol). The mixture was degassed bybubbling nitrogen into the solution for 10 min. The pressure bottle wasclosed and heated at 90° C. for 3 h. The solvent was removed underreduced pressure and the residue was purified via Biotage (lineargradient 0-20%, methanol/ethyl acetate; 25M column) to afford titlecompound 286 as a brown solid (1.52 g, 7.63 mmol, 79%). MS (m/z): 200.1(M+H).

Step 2. 3-(dimethylphosphoryl)aniline (287)

To a solution of compound 286 (1.5 g, 7.5 mmol) in methanol (62 ml) andwater (12 ml) under nitrogen at room temperature was added ammoniumchloride (0.604 g, 11.3 mmol) and iron (1.68 g, 30.1 mmol). Theresulting mixture was heated to reflux for 30 min then filtered throughcelite. The celite pad was rinsed with methanol. The filtrate andwashings were combined and concentrated and the residue was purified viaBiotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) toafford compound 287 as a yellow solid (1.27 g, 7.51 mmol, quantitative).MS (m/z): 170.1 (M+H).

Step 3.tert-butyl(6-(7-(4-(3-(3-(dimethylphosphoryl)phenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(288)

To a solution of compound 126 (schemes 6 or 9) (200 mg, 0.381 mmol) indry tetrahydrofuran (8 mL) under nitrogen at −20° C. was added4-nitrophenyl chloroformate (115 mg, 0.572 mmol). The reaction mixturewas stirred at −20° C. for 2 h. A solution of3-(dimethylphosphoryl)aniline 287 (97 mg, 0.57 mmol) andN,N′-diisopropylethylamine (0.200 mL, 1.14 mmol) in a mixture of drytetrahydrofuran (2 mL) and dry N,N′-dimethylformamide (2 mL) were addedat −20° C., the reaction mixture was allowed to warm to room temperatureslowly, and the stirring was continued for an additional 16 h. Thesolvent was removed under reduced pressure; the residue was diluted withethyl acetate, washed with a saturated aqueous solution of ammoniumchloride, dried over anhydrous sodium sulfate and concentrated.Purification via Biotage (linear gradient 0-20%,methanol/dichloromethane; 25M column) afforded compound 288 (230 mg,0.32 mmol, 84%). MS (m/z): 720.4 (M+H).

Step 4.1-(3-(dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(289)

To a solution of compound 288 (230 mg, 0.32 mmol) in dichloromethane (7mL) under nitrogen at room temperature was added trifluoroacetic acid(2.5 mL, 32 mmol). The reaction mixture was stirred for 16 h at roomtemperature. The solvent was removed under reduced pressure and asaturated aqueous solution of sodium bicarbonate was added. The aqueousphase was extracted with ethyl acetate (3×), the combined organic layerswere concentrated. The residue was purified via Biotage (linear gradient0-20%, methanol/dichloromethane; 25M column) to afford compound 289 asan off-white solid (75.3 mg, 0.122 mmol, 38.0%). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 9.15 (s, 1H), 9.06 (s, 1H), 8.57 (d, J=1.6 Hz, 1H),8.53 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.92-7.83(m, 2H), 7.76 (dd, J=13.2, 2.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.49-7.42 (m,2H), 7.41-7.33 (m, 1H), 7.32-7.26 (m, 1H), 6.67 (d, J=5.6 Hz, 1H), 3.78(s, 2H), 3.54-3.34 (2H, hidden under water signal), 3.24 (s, 3H), 2.65(t, J=5.6 Hz, 2H), 1.65 (d, J=13.2 Hz, 6H). MS (m/z): 620.4 (M+H).

Example 1801-(4-(Dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(290)

Compound 290 was obtained by following the procedures described abovefor the compound 289 (Example 179). Characterization of compound 290 andcompounds 295-300 are provided in the Table 1.

TABLE 1 Cpd Ex STRUCTURE CHARACTERIZATION 290 180

1-(4-(dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (400 MHz, DMSO-d₆) δ (ppm); 9.38(s, 1H), 9.29 (s, 1H), 8.57 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.32 (s,1H), 8.23 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.77 (d, J =13.4 Hz, 1H), 7.70-7.65 (m, 2H), 7.62- 7.59 (m, 2H), 7.46 (t, J = 8.8Hz, 1H), 7.28 (d, J = 10.0 Hz, 1H), 6.67 (d, J = 5.6 Hz, 1H), 3.78 (s,2H), 3.40 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J = 5.8 Hz, 2H),1.61 (d, J = 13.2 Hz, 6H), one NH is not seen in the spectrum. MS (m/z):620.3 (M + H). 295 185

1-(4-(2-(5-5,8,11-Trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):1H: 9.54 (s, 1H); 9.03 (s, 1H); 8.58-8.56 (m, 2H); 8.51 (d, J = 5.5,1H); 8.31 (s, 1H); 8.22 (d, J = 8.4, 1H); 7.88 (dd, J = 7.8, 1.8, 1H);7.76 (dd, J = 12.9, 2.4, 1H); 7.53-7.41 (m, 3H); 7.26- 7.24 (m, 1H);6.66 (d, J = 5.5, 1H); 3.78 (s, 2H); 3.50-3.44 (m, 8H); 3.40- 3.37 (m,2H); 3.20 (s, 3H); 2.66-2.62 (m, 2H). MS (M/Z): (calc.) 718.2 (found)718.4 296 186

N1-(4-(2-(5-5,8,11-Trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N3-methyl-N3-phenylmalonamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1H: 10.29(s, 1H); 8.55 (d, J = 1.4, 1H); 8.49 (d, J = 5.5, 1H); 8.30 (s, 1H);8.21 (d, J = 7.8, 1H); 7.87 (dd, J = 8.2, 1H); 7.77 (d, J=12.5, 1H);7.49-7.29 (m, 7H); 6.64 (d, J = 5.3, 1H); 3.76 (s, 2H); 3.50- 3.43 (m,8H); 3.41-3.38 (m, 2H); 3.22-3.18 (m, 8H); 2.63 (t, J = 5.9, 2H). MS(M/Z): (calc.) 688.3 (found) 688.5 297 187

1-(4-(2-(5-5,8,11-Trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1H: 9.69 (s,1H); 9.25 (s, 1H); 8.58 (s, 1H); 8.52 (d, J = 5.3, 1H); 8.32 (s, 1H);8.23 (d, J = 8.0, 1H); 7.92- 7.88 (m, 1H); 7.74 (dd, J = 13.1, 2.5, 1H);7.47 (t, J = 9.0, 1H); 7.30-7.26 (m, 1H); 6.66 (d, J = 5.9, 1H); 6.56(d, J = 0.9, 1H); 3.80 (s, 2H); 3.52-3.47 (m, 8H); 3.42-3.38 (m, 2H);3.22 (s, 3H); 2.68-2.64 (m, 2H); 2.37 (d, J = 1.0, 3H). MS (M/Z):(calc.) 637.2 (found) 637.4 300 190

(E)-1-(3-Fluoro-4-(2-(5-((4-methylpiperazin-1-ylimino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 1H: 9.73 (s, 1H); 9.20 (d, J = 2.5, 1H); 8.75 (d,J = 2.0, 1H); 8.57 (dd, J = 7.7, 2.2, 1H); 8.53 (d, J = 5.5, 1H); 8.33(s, 1H); 8.26-8.24 (m, 2H); 8.06 (dd, J = 8.4, 2.0, 1H); 7.78 (dd, J =13.1, 2.5, 1H); 7.69 (s, 1H); 7.54-7.43 (m, 3H); 7.30- 7.26 (m, 1H);6.67 (d, J = 5.5, 1H); 5.76 (s, 2H); 3.22-3.16 (m, 4H); ~2.54 (m, 4H?,obscured by DMSO peak); 2.24 (s, 3H). MS: (calc.) 668.2 (found) 668.3(MH)+

Example 202 Step 1.tert-Butyl(2-(7-(2-fluoro-4-(3-isopropylureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(314)

The reaction mixture of aniline 46 (200 mg, 0.379 mmol) and2-isocyanatopropane (64.5 mg, 0.758 mmol) was heated to 100° C. for 15min in a microwave reactor. The reaction mixture was loaded directlyinto Biotage (Silicycle, HR, 12 g column, 50-100% EA/Hexane, thenMeOH/EA, 0-20%). The collected fractions afforded the desired product314 (150 mg, 0.245 mmol, 64.6% yield) as a white solid. MS: 613(MH)⁺,very weak signal.

Step 2.1-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-isopropylurea(315)

The solution of urea 314 (150 mg, 0.245 mmol) and TFA (1 mL, 12.98 mmol)in DCM (20 mL) was stirred 4 hr at room temperature and concentrated.The residue was partitioned between EtOAc/NaHCO₃ sat. solution. Thesolid was collected by filtration and combined with organic layer. Themixture was concentrated and the residue was purified via Biotage(EA/MeOH 0-40%, 12 g Silicycle HR column). Collected fractions gave thedesired product 315 (70 mg, 0.137 mmol, 55.8% yield) as a white solid.¹HNMR (dmso-d₆) δ(ppm) 1H:8.67(s, 1H), 8.48(d, 1H, J=5.5 Hz), 7.91(s,1H), 7.65(dd, 1H, J1=13.7 Hz, J2=2.6 Hz), 7.32(t, 1H, J=9.0 Hz),7.07(m,2H), 6.63(d, 1H, J=5.5 Hz), 6.13(d, 1H, J=7.6 Hz), 4.04(s, br, 2H),3.08(s, 3H), 3.72(m, 1H), 3.47(t, 2H, J=5.2 Hz), 3.24(s, 3H), 2.94(m,2H), 1.07(s, 3H, 1.05(s, 3H) (presumably a mono-TFA salt). MS:513.4(MH)⁺

Step 4.4-(2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline(319) Step 1. 2-Bromo-5-(1,3-dioxan-2-yl)pyridine (316)

To a solution of 6-bromopyridine-3-carbaldehyde (25 g, 134 mmol) intoluene (130 mL) were added 1,3-propanediol (20.45 g, 269 mmol) and10-camphorsulfonic acid (3.12 g, 13.44 mmol). The reaction mixture washeated to reflux, with azeotropic removal of the evolved water, for 50minutes, cooled down to r.t. and concentrated. The residue waspartitioned between EtOAc (150 mL) and saturated aqueous NaHCO₃ solution(100 mL). Organic phase was collected and the aqueous phase wasextracted with EtOAc (2×150 mL). Combined organic fractions were washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated toyield a brown solid which was triturated with Et₂O and hexane (10/200mL), to afford intermediate 316 (27.7 g, 84% yield) as a beige solid. MS(m/z): 244.1, 246.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.40 (d,J=2.4 Hz, 1H), 7.35 (dd, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.0, 0.4 Hz,1H), 5.61 (s, 1H), 4.15 (ddd, J=11.8, 5.0, 1.2 Hz, 2H), 3.98-3.91 (m,2H), 2.028-1.95 (m, 1H), 1.46 (d quint, J=13.2, 1.2 Hz, 1H).

Step 2.2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-chlorothieno[3,2-b]pyridine (317)

To a solution of 7-chlorothieno[3,2-b]pyridine (1) (13.33 g, 79 mmol) inTHF (204 mL) at −5° C./−10° C. was added n-BuLi (2.5 M in hexanes, 31.6mL, 79 mmol) over 50 min. After 30 min, a solution of zinc chloride inether (1M, 79 mL, 79 mmol) was added at −5° C./−10° C. over 50 min andthe reaction mixture was allowed to warm-up to r.t. After 45 min,2-bromo-5-(1,3-dioxan-2-yl)pyridine (316) (15.98 g, 65.5 mmol) andpalladium tetrakistriphenylphosphine (2.27 g, 1.964 mmol) in THF (28 mL)were added and the mixture was heated to reflux for 2 h, cooled down tor.t., and concentrated. The residue was diluted with DCM (600 mL), H₂O(500 mL) and NH₄OH (100 mL), stirred at r.t. for 1 h and the phases wereseparated. The aqueous phase was extracted with DCM (2×100 mL); thecombined organic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was triturated with MTBE (150 mL), to affordintermediate 317 (12.796 g, 59% yield) as a beige solid. ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.66-8.65 (m, 2H), 8.43 (d, J=0.8 Hz, 1H), 8.30(d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=5.0, 0.6 Hz, 1H),5.68 (s, 1H), 4.19 (dd, J=11.6, 4.8 Hz, 2H), 3.99 (t, J=11.4 Hz, 2H),2.07-2.01 (m, 1H), 1.49 (d, J=13.2 Hz, 1H). MS (m/z): 333.1 (M+H).

Step 3.2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(318)

To a suspension of 317 (22.48 g, 67.5 mmol) in phenyl ether (65 mL) wasadded sodium carbonate (14.32 g, 135 mmol) and 2-fluoro-4-nitrophenol(15.92 g, 101 mmol). The reaction mixture was heated at 180° C. for 2 h,cooled down to 40° C., diluted with DCM (300 mL), stirred at r.t. for 15min and filtered. The filtrate was collected and concentrated to aminimal volume; Et₂O (200 mL) was added and the formed suspension wasstirred for 30 min. The solid material was collected by filtration, toafford intermediate 318 (25.20 g, 55.6 mmol, 82% yield) as a beigesolid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.63-8.62 (m, 2H), 8.48 (dd,J=10.6, 2.6 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (dt,J=8.8, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.71 (t, J=8.6 Hz,1H), 6.98 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.19 (dd, J=10.8, 5.2 Hz,2H), 3.98 (td, J=12.0, 2.0 Hz, 2H), 2.08-1.99 (m, 1H), 1.46 (d, J=13.6Hz, 1H). MS (m/z): 454.2 (M+H).

Step 4.4-(2-(5-(1,3-dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline(319) Method A

To a suspension of 318 (10 g, 22.05 mmol) in EtOH (216 ml) and water(108 ml) was added iron powder (10.47 g, 187 mmol) and ammonium chloride(1.015 g, 18.97 mmol). The mixture was heated to reflux for 30 min,filtered while hot and the solids were washed with ether (200 mL). Thefiltrate and washings were combined and concentrated to afford titlecompound 319 (9.62 g, 99% yield) as a beige solid. This material wasused in the next step (Scheme 18) without additional purification. ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.64 (d, J=2.0 Hz, 1H), 8.51 (dd, J=5.6,2.0 Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.0, 0.8 Hz, 1H), 7.93 (dd,J=8.4, 2.0 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 6.61 (dd, J=5.4, 0.6 Hz,1H), 6.54 (dd, J=13.2, 2.4 Hz, 1H), 6.46 (ddd, J=8.8, 2.8, 0.6 Hz, 1H),5.67 (s, 1H), 5.56 (s, 2H), 4.19 (dd, J=10.6, 5.0 Hz, 2H), 3.98 (td,J=12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1H), 1.49 (dt, J=13.2, 1.3 Hz, 1H).MS (m/z): 424.1 (M+H).

Method B

To a solution of 4-amino-2-fluorophenol (7.42 g, 58.4 mmol) in DMSO (65mL) was added potassium tert-butoxide (7.75 g, 69.0 mmol)). After 30min, intermediate 317 (17.67 g, 53.1 mmol) was added and the reactionmixture was heated at 100° C. for 1.5 h, cooled down to roomtemperature, poured in water (300 mL) at 40-45° C. and stirred for 30min. The solid was collected by filtration, washed with water (2×30 mL)and dried for 2 h. This material was triturated with ether (60 mL), toafford title compound 319 (19.80 g, 88% yield) as a brown solid. MS(m/z): 424.1 (M+H).

Example 2031-(4-(2-(5-5,8,11,14-Tetraoxa-2-azapentadecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea(323) Step 1:1-(4-(2-(5-(1,3-Dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea(320)

A 100 mL round bottom flask was charged with 319 (0.55 g, 1.3 mmol) andDIPEA (0.91 mL, 5.2 mmol) in dry tetrahydrofuran (55 mL) to give acolorless solution. The reaction mixture was cooled to 0° C. thentriphosgene (0.154 g, 0.520 mmol) was added. The reaction mixture wasstirred for 1 h at 0° C. then cyclopropylamine (1.8 mL, 26 mmol) wasadded.

Finally the reaction mixture was stirred at r.t. for 3 h thenconcentrated. The residue was partitioned between water and ethylacetate, resulting in the formation a thick white solid. This wasisolated by suction filtration, rinsed with water and ethyl acetate, anddried in vacuo to give crude 320 (0.65 g, 1.2 mmol, 99% yield) which wasused without further purification. MS: 507.2 (M+H).

Step 2: 1-Cyclopropyl-3-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-yloxy)phenyl)urea(321)

A suspension of 320 (0.65 g, 1.3 mmol) in 5:2:1 acetone/water/TFA (100mL) was heated to reflux for 6 h. The mixture was then cooled andconcentrated. The resulting solid residue was suspended in water,isolated by suction filtration, washed with ethyl acetate and dried invacuo yielding 321 (0.49 g, 1.1 mmol, 85% yield) which was used withoutfurther purification in the next step. MS: 449.0 (M+H).

Step 3. 2,5,8,11-Tetraoxatridecan-13-amine (322)

Tetraethylene glycol monomethyl ether (10.0 mL, 47.5 mmol), phthalimide(7.20 g, 48.9 mmol), and triphenylphosphine (12.8 g, 48.8 mmol) weresuspended in dry tetrahydrofuran (200 mL) to give a colorlesssuspension. Diethyl azodicarboxylate (8.0 mL, 50.5 mmol) was addeddropwise by syringe, and the mixture was stirred at r.t. for 18 h. Thenethanol (50 mL) was added, the mixture was stirred for a further 30 minand then concentrated under reduced pressure. The residue was dissolvedin 1:1 ethyl acetate/hexanes (100 mL), stirred at 0° C. for 2 h, and theresulting white precipitate was removed by suction filtration. Thefiltrate was concentrated (13.5 g, 40.0 mmol, 84% yield) and used in thenext step without further purification.

The above crude product was dissolved in ethanol (100 mL) to give acolorless solution. Hydrazine hydrate (2.3 mL, 40 mmol) was added andthe mixture was heated to reflux for 4 h. It was then cooled,concentrated HCl (10.0 mL) was added, and the mixture refluxed for 1hour more. It was then was cooled to r.t., the white precipitate removedby suction filtration, and the filtrate concentrated. The residue waspartitioned between water and diethyl ether. The aqueous phase wasextracted with ether (organic phase, containing mostly PPh₃O by MS, wasdiscarded), then basified with 3M NaOH (50 mL) to pH=13. The aqueousphase was saturated with sodium chloride and extracted repeatedly withdichloromethane (˜10×50 mL). The organic extract was dried (MgSO₄) andconcentrated to yield 322 (7.0 g, 33.8 mmol, 84% yield, 71% over 2steps). This was used without further purification in subsequent step.MS (m+1)=208.1.

Step 4:1-(4-(2-(5-5,8,11,14-Tetraoxa-2-azapentadecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea(323)

To a suspension of carboxaldehyde 321 (0.45 g, 1.0 mmol) and amine 322(1.4 g, 6.75 mmol) in dichloromethane (75 mL) was added acetic acid(0.12 mL, 2.0 mmol). The reaction mixture was stirred for 1 h, thensodium triacetoxyborohydride (0.64 g, 3.0 mmol) was added and theresulting mixture stirred for 18 h. The mixture was then partitionedbetween water and dichloromethane, washed with 1M NaOH and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by Gilson reverse phase HPLC (35-75% MeOH/H₂O, Aquasil C₁₈,30 min) and lyophilized. The purified product (containing some formicacid from the HPLC) was partitioned between warm dichloromethane and 1MNaOH. The organic phase was dried (MgSO₄), filtered and concentrated togive title compound 323 (0.264 g, 0.413 mmol, 41.1% yield). ¹H NMR(DMSO-d₆) δ(ppm) ¹H: 8.80 (s, 1H); 8.57 (s, 1H); 8.51 (d, J=5.5, 1H);8.31 (s, 1H); 8.23 (d, J=8.0, 1H); 7.89 (dd, J=8.0, 1.5, 1H); 7.73 (dd,J=13.5, 2.2, 1H); 7.38 (t, J=9.0, 1H); 7.20 (d, J=8.2, 1H); 6.67 (d,J=2.7, 1H); 6.64 (d, J=5.5, 1H); 3.78 (s, 2H); 3.56-45 (m, 12H); 3.41(t, J=5.7, 2H); 3.21 (s, 3H); 2.66 (d, J=5.7, 2H); 2.58-2.51 (m, 1H);0.66-0.62 (m, 2H); 0.44-0.41 (m, 2H). LRMS: 640.5 (M+H).

324: Example 204 Example 204(S)-2-amino-6-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methylamino)hexanoicacid (324)

To a suspension of 321 (0.26 g, 0.58 mmol) and N-Boc-lysine (1.1 g, 4.6mmol) in dichloromethane (75 mL) and was added acetic acid (0.066 mL,1.2 mmol). The reaction mixture was stirred for 1 h, then sodiumtriacetoxyborohydride (0.37 g, 1.7 mmol) was added and the resultingmixture stirred for 18 h. The mixture was then partitioned between waterand dichloromethane, and the solid precipitate removed by suctionfiltration through celite. The product was mostly in the solid filtercake, so this was solubilized by washing with 1:1dichloromethane/methanol. This solution was concentrated and the residuewas purified by Gilson reverse phase HPLC (35-75% MeOH/H₂O, Aquasil C₁₈,30 min) and lyophilized to yield BOC-protected product. This wasdissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL),and stirred at r.t. for 3 h. The mixture was concentrated and theresidue was purified by Gilson reverse phase HPLC (35-75% MeOH/H₂O,Aquasil C₁₈, 30 min) and lyophilized to yield title compound 324 (44 mg,69% yield). ¹H NMR (DMSO-d₆) δ(ppm) ¹H: 9.02 (s, 1H); 8.66 (s, 1H); 8.53(d, J=5.3, 1H); 8.35 (s, 1H); 8.28 (d, J=8.4, 1H); 7.98 (d, J=6.3, 1H);7.72 (dd, J=13.5, 2.3, 1H); 7.37 (t, J=9.0, 1H); 7.21 (d, J=10.0, 1H),6.89 (s, 1H); 6.68 (d, J=5.3, 1H); 4.00 (s, 2H); 2.75-2.70 (m, 2H);2.55-2.52 (m, 1H); 2.45 (m, 1H); 1.70-1.30 (m. 6H); 0.67-0.62 (m, 2H);0.44-0.40 (m, 2H). LRMS: 579.5 (M+H).

Example 2051-Cyclopropyl-3-(3-fluoro-4-(2-(5-((2-(2-methoxyethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaStep 1:6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinaldehyde(325)

A suspension of 318 (2.64 g, 5.82 mmol) in 80% aqueous acetic acid (42mL) was heated at 90° C. for 18 h. The reaction mixture was cooled tor.t. and diluted with water. The resulting precipitate was collected bysuction filtration. The solid was transferred to a round-bottomed flask,the remaining water was removed by azeotropic distillation with toluene(4 times), and the solid dried in vacuo yielding 325 (1.76 g, 76%). LRMS(M+H): 396.3

Step 2: 2-(2-methoxyethoxy)ethanamine (326)

Diethylene glycol monomethyl ether (9.8 mL, 83 mmol), phthalimide (14.7g, 100 mmol), and triphenylphosphine (26.2 g, 100 mmol) were suspendedin dry tetrahydrofuran (200 mL) to give a colorless suspension (seescheme 18, step 3). Diethyl azodicarboxylate (15.8 mL, 100 mmol) wasadded dropwise by syringe, and the mixture was stirred at r.t. for 18 h.Then ethanol (50 mL) was added, the mixture was stirred for a further 30min and then concentrated under reduced pressure. The residue wasdissolved in 1:1 ethyl acetate/hexanes (100 mL), stirred at 0° C. for 2h, and the resulting white precipitate was removed by suctionfiltration. The filtrate was concentrated and used in the next stepwithout further purification.

The above crude product was dissolved in ethanol (200 mL) to give acolorless solution. Hydrazine hydrate (5.1 mL, 104 mmol) was added andthe mixture was heated to reflux for 4 h. It was then cooled,concentrated HCl (16 mL) was added, and the mixture refluxed for 1 hourmore. It was then was cooled to r.t., the white precipitate removed bysuction filtration, and the filtrate concentrated. The residue waspartitioned between water and ethyl acetate. The aqueous phase wasextracted with ethyl acetate (organic phase, containing mostly PPh₃O byMS, was discarded), then basified with 3M NaOH (50 mL) to pH=13. Theaqueous phase was saturated with sodium chloride and extractedrepeatedly with dichloromethane (˜10×50 mL. The organic extract wasdried (MgSO₄) and concentrated to yield 326 (6.6 g, 56 mmol, 67% yieldover 2 steps). This was used without further purification in subsequentreaction. MS (m+1)=120.2.

Step 3:N-((6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-2-(2-methoxyethoxy)ethanamine(327)

A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g,2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml)was stirred for 1 h at room temperature. Then sodiumtriacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t.for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) wasthen added, and stirring continued for 2 h. The reaction mixture waspartitioned between dichloromethane and 1N NaOH. The yellow suspensionwas removed by filtration and rinsed with dichloromethane and 1N NaOH.The organic extract was dried over anhydrous sodium sulfate, filtered,and concentrated. The residue was purified via Biotage (linear gradient0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4

Step 4:tert-butyl(6-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-(2-methoxyethoxy)ethyl)carbamate(328)

To compound 327 (0.28 g, 0.56 mmol) in dichloromethane (100 mL) at roomtemperature was added triethylamine (0.25 mL, 1.7 mmol), DMAP (0.017 g,0.14 mmol) and Boc₂O (0.26 g, 1.1 mmol). The reaction mixture wasstirred at room temperature for 2 h, then the mixture was washedsequentially with water, saturated ammonium chloride, and brine, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel chromatography (ethyl acetate) toafford compound 328 (0.20 g, 60% yield). LRMS (M+H): 599.5

Step 5:tert-butyl(6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-(2-methoxyethoxy)ethyl)carbamate(329)

To nitro compound 328 (0.20 g, 0.33 mmol) in MeOH (75 mL) was added irondust (0.37 g, 6.7 mmol) and ammonium chloride (0.089 g, 1.7 mmol) inwater (5 mL). The resulting mixture was heated to reflux for 4 h, thencooled, filtered through celite and concentrated. The residue waspartitioned between ethyl acetate and water, washed with brine, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theproduct 329 (0.18 g, 95%) was used crude in the next step. LRMS (M+H):569.5

Step 6:tert-butyl(6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-(2-methoxyethoxy)ethyl)carbamate(330)

To amine 330 (0.17 g, 0.30 mmol) and DIPEA (0.16 mL, 0.12 g, 0.90 mmol)in tetrahydrofuran (25 mL) at 0° C. was added triphosgene (0.035 g, 0.12mmol) and the resulting solution was stirred for 1 h at 0° C.Cyclopropylamine (0.26 g, 4.6 mmol) was added and the mixture was warmedto room temperature and stirred for 18 h, then concentrated underreduced pressure. The residue was partitioned between dichloromethaneand water, the organic phase was washed with sat. NH₄Cl_((aq)) andbrine, dried over MgSO₄, filtered and concentrated, yielding crude 330(0.15 g, 77% yield). LRMS (M+H): 652.6

Step 7:1-Cyclopropyl-3-3-fluoro-4-(2-(5-((2-(2-methoxyethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(331)

Compound 330 (0.15 g, 0.23 mmol) was dissolved in dichloromethane (20mL) and trifluoroacetic acid (0.9 mL) and the reaction mixture wasstirred for 12 h at r.t. The mixture was concentrated and the residuewas purified by Gilson reverse phase HPLC (40-80% MeOH/H₂O, Aquasil C₁₈,30 min) and lyophilized. The purified product (containing some formicacid from the HPLC) was partitioned between warm dichloromethane and 1MNaOH. The organic phase was dried (MgSO₄), filtered and concentrated togive title compound 331 (0.110 g, 72% yield) (a mono-TFA salt despitethe treatment with NaOH). ¹H NMR (DMSO-d₆) δ(ppm) ¹H: 8.84 (s, 1H); 8.65(d, J=1.3, 1H); 8.53 (d, J=5.5, 1H); 8.37 (s, 1H); 8.30 (d, J=8.2, 1H);7.99 (dd, J=8.2, 2.0, 1H); 7.73 (dd, J=13.7, 2.5, 1H); 7.38 (t, J=9.0,1H); 7.22-7.18 (m, 1H); 6.68-6.64 (m, 2H); 4.03 (s, 2H); 3.60-3.52 (m,4H); 3.48-3.44 (m, 2H); 3.25 (s, 3H); 2.92-2.88 (m, 2H); 2.55 (septet,J=3.1, 1H); 0.69-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: (M+H): 552.5.

Examples 206 and 2074-((6-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methylamino)butanoicacid (332), and1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-oxopyrrolidin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(333)

To a suspension of carbaldehyde 321 (0.20 g, 0.45 mmol) and4-aminobutyric acid (1.0 g, 9.7 mmol) in dichloromethane (75 mL) and wasadded acetic acid (0.051 mL, 0.89 mmol). The reaction mixture wasstirred for 1 h, then sodium triacetoxyborohydride (0.38 g, 1.8 mmol)was added and the resulting mixture stirred for 18 h. The mixture wasthen partitioned between water and dichloromethane, and the solidprecipitate removed by suction filtration through celite. MS analysisindicated the cyclized product 333 was in the filtrate, while the acidproduct 332 was mostly in the solid filter cake. The organic phase fromthe filtrate was concentrated and the residue purified by silica gelchromatography (10% MeOH/ethyl acetate) to provide purified 333 (35 mg,15% yield). The product in the celite filter cake was solubilized bywashing with 1:1 dichloromethane/methanol. This solution wasconcentrated and the residue was purified by Gilson reverse phase HPLC(35-75% MeOH/H₂O, Aquasil C₁₈, 30 min) and lyophilized to afford acid332 (44 mg, 69% yield). Characterization of compounds 332 and 333 isprovided below.

Compound 332 (example 206): ¹H NMR (DMSO-d₆) δ(ppm) ¹H: 9.23 (s, 1H);8.58 (s, 1H); 8.51 (d, J=5.4, 1H); 8.36 (s, 1H); 8.32 (s, 1H); 8.24 (d,J=8.2, 1H); 7.91 (dd, J=8.4, 2.0, 1H); 7.74 (dd, J=13.7, 2.3, 1H); 7.37(t, J=9.0, 1H); 7.22 (d, J=9.0, 1H); 6.63 (d, J=5.3, 1H); 3.79 (s, 2H);2.56 (t, J=5.1, 2H); 2.47-2.43 (m, 1H); 2.27 (t, J=7.2, 2H); 1.65(quint, J=6.7, 2H); 0.66-0.61 (m, 2H); 0.44-0.40 (m, 2H). LRMS: (M+H)536.4.

Compound 333 (example 207): ¹H NMR (DMSO-d₆) δ(ppm) ¹H: 8.76 (s, 1H);8.52 (s, 1H); 8.52 (d, J=5.5, 1H); 8.35 (s, 1H); 8.26(d, J=8.2, 1H);7.79 (dd, J=8.2, 2.1, 1H); 7.73 (dd, J=13.5, 2.5, 1H); 7.38 (t, J=9.2,1H); 7.20 (d, J=8.4, 1H); 6.65 (d, J=5.3, 1H); 6.62 (s, 1H); 4.46 (s,2H); 3.30-3.20 (t, 2H, obscured by water peak?); 2.55 (quint, J=3.3,1H); 2.31 (t, J=7.8, 2H); 1.95 (quint, J=7.6, 2H); 0.67-0.62 (m, 2H);0.45-0.40 (m, 2H). LRMS: (M+H) 518.4

Examples 208 and 209 Step 1.(5)-1-cyclopropyl-3-(3-fluoro-4-(2-(5-((1-methoxypropan-2-ylamino)methyl)-pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(334)

To a stirred suspension of carbaldehyde 321 (336 mg, 0.749 mmol),(S)-1-methoxy-2-aminopropane (200 mg, 2.248 mmol) and acetic acid (68mg, 1.124 mmol) in DCM (20 ml) at rt under nitrogen was added NaBH(OAc)₃(418 mg, 1.873 mmol). The reaction mixture was stirred at rt overnightand quenched with a solution of 10% HCl. The layers were separated; theaqueous layer was collected, washed twice with DCM and basified with 4NNaOH (pH 12) to form a suspension that was stirred for 30 min. The solidwas collected by filtration, rinsed with water and air-dried andpurified by flash column chromatography on silica gel (eluent 2% ofammonium hydroxyde in MeOH/DCM: 10/90) to afford the title compound 334(182 mg, 0.35 mmol, 46% yield) as a yellow fluffy solid. ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.71 (s, 1H), 8.58 (d, J=1.6 Hz, 1H). 8.51 (d,J=5.5 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.91 (dd, J=8.2,2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H),7.23-7.17 (m,1H), 6.64 (d, J=5.5 Hz, 1H), 6.57 (bd, J=2.7 Hz, 1H), 3.84(d, J=14.5 Hz, 1H), 3.78 (d, J=14.5 Hz, 1H), 3.27 (dd, J=9.4, 6.3 Hz,1H), 3.24 (s, 3H), 3.19 (dd, J=9.2, 5.5 Hz, 1H), 2.81-2.71 (m, 1H),2.59-2.51 (m, 1H), 2.36-2.10 (m,1H), 0.98 (d, J=6.3 Hz, 3H), 0.69-0.62(m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 522.4 (M+H).

Step 2.(S)-N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(1-methoxypropan-2-yl)acetamide(335)

A suspension of urea 334 (66 mg, 0.127 mmol) in acetic anhydride (2 ml)was stirred at rt for 2 days. The reaction mixture was quenched byaddition of methanol and water, and partitioned with AcOEt. Afterseparation, the organic layer was collected, washed with water, 1N NaOH(×4), water and brine, dried over anhydrous magnesium sulfate, filteredand concentrated. The crude solid was purified by flash columnchromatography on silica gel (eluent 2% of ammonium hydroxyde inMeOH/DCM: 05/90 to 10/90) to afford the title compound 335 (46 mg, 0.08mmol, 64% yield) as an off-white fluffy solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): mixture of rotamers, 8.70 (s, 1H), 8.58-8.48 (m, 2H), 8.34 and8.30 (2s, 1H), 8.27 and 8.19 (2d, J=8.3 Hz, 1H), 7.85-7.69 (m, 2H), 7.38(t, J=9.0 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.67-6.54 (m, 2H), 4.74-4.16(m, 3H), 3.41-3.22 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.59-2.52 (m, 1H),2.16 and 1.96 (2s, 3H), 1.09 and 1.04 (2d, J=6.9 Hz, 3H), 0.72-0.58 (m,2H), 0.50-0.36 (m, 2H). MS (m/z): 564.4 (M+H).

Example 210N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)cyclopropanecarboxamide(337) Step 1.tent-Butyl(6-(7-(4-(cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(336)

To a solution of aniline 126 (200 mg, 0.36 mmol) in DCM (10 mL) undernitrogen at 0° C. were added DIPEA (127 μl, 0.72 mmol) andcyclopropylcarbonyl chloride (50 □l, 0.54 mmol). The reaction mixturewas allowed to warm-up to room temperature slowly and stirred overnightat room temperature. The reaction mixture was diluted in AcOEt, andsuccessively washed with a saturated aqueous solution of ammoniumchloride (×4), 1N NaOH (×2), water and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The crude residue wascoprecipitated in a minimum of AcOEt in hexanes. The solid was collectedby filtration, rinsed with hexanes, air-dried and dried under highvacuum to afford the title compound A (quantitative yield) as a palebrown solid. MS (m/z): 593.4 (M+H).

Step 2.N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)cyclopropanecarboxamide(337)

To a solution of amide 336 (215 mg, crude mixture) in DCM (10 mL) wasadded TFA (2 ml). The reaction mixture was stirred at room temperaturefor 2 h., concentrated, partitioned between water and AcOEt, andbasified with 1N NaOH solution. After separation of layers, the organiclayer was collected, washed with 1N NaOH (×2), water and brine, driedover anhydrous magnesium sulfate, filtered and concentrated. The residuewas purified by flash column chromatography on silica gel (eluent 2% ofammonium hydroxyde in MeOH/DCM: 05/95 to 15/95) to afford the titlecompound 336 (87 mg, 0.177 mmol, 48% yield) as a salmon sticky solid. ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 10.57 (s, 1H), 8.57 (d, J=1.6 Hz, 1H),8.52 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.93-7.83(m, 2H), 7.47 (t, J=8.9 Hz, 1H), 7.41 (dd, J=8.9, 2.0, 1H), 6.66 (d,J=5.3 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 2.66(t, J=5.7 Hz, 2H), 1.79 (quint., J=6.2 Hz, 1H), 0.90-0.80 (m, 4H), oneNH is missing. MS (m/z): 493.4 (M+H).

Examples 340 and 341Methyl(6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(340) and(R)-2-amino-N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)-3-methylbutanamide(341) Step 1:tert-Butyl(6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(338)

To amine 126 (0.24 g, 0.46 mmol) in tetrahydrofuran (60 mL) at 0° C. wasadded triphosgene (0.054 g, 0.18 mmol) and the resulting solution wasstirred for 1 h at 0° C. DIPEA (0.40 mL, 0.30 g, 2.3 mmol) andcyclopropylamine (0.26 g, 4.6 mmol) were sequentially added and themixture was warmed to room temperature and stirred for 3 h, thenconcentrated under reduced pressure. The residue was partitioned betweendichloromethane and water, the organic phase was collected, washed withsat. NH₄Cl_((aq)) and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (ethyl acetate to 5% methanol/ethyl acetate), yielding 338 (0.19 g,67% yield). MS (m/z): 608.4 (M+H).

Step 2:1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(339)

To 338 (0.19 g, 0.31 mmol) in dichloromethane (40 mL) was added TFA (3mL). The solution was stirred for 6 h, then concentrated. The residuewas partitioned between 98:2 dichloromethane/methanol mixture and 1MNaOH(aq), washed with brine, dried over MgSO₄, filtered andconcentrated. The resulting oil was triturated with diethyl ether andethyl acetate providing 339 (0.13 g, 82% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): ¹H: 8.80 (s, 1H); 8.57 (s, 1H); 8.51 (d, J=5.5, 1H);8.31 (s, 1H); 8.23 (d, J=8.0, 1H); 7.89 (dd, J=8.0, 1.5, 1H); 7.73 (dd,J=13.5, 2.2, 1H); 7.38 (t, J=9.0, 1H); 7.20 (d, J=8.2, 1H); 6.66-6.62(m, 2H); 3.78 (s, 2H); 3.41 (t, J=5.7, 2H); 3.24 (s, 3H); 2.65 (d,J=5.7, 2H); 2.57-2.51 (m, 1H); 0.66-0.62 (m, 2H); 0.44-0.41 (m, 2H). MS(m/z): 508.3 (M+H).

Step 3.Methyl(6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(340)

To a solution of compound 339 (220 mg, 0.433 mmol) and methylchloroformate (50.2 μl, 0.65 mmol) in THF (4 ml) was added DIPEA (227μl, 1.30 mmol) and the mixture was stirred at room temperature for 18 h.The solvent was removed under reduced pressure, the residue wastriturated with MeOH and the solid suspension was collected byfiltration and purified via Biotage (linear gradient 0-20%,methanol/dichloromethane; Snap 25 g column) to afford compound 340(123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.70 (s, 1H), 8.56-8.50 (m, 2H), 8.33 (s, 1H), 8.25(d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H),7.38 (t, J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.6 Hz,1H), 6.56 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H),3.22 (s, 2H), 2.59-2.51 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H).MS (m/z): 566.1 (M+H).

Step 4:(R)-2-amino-N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)-3-methylbutanamide(341)

To a solution of 339 (48 mg, 0.095 mmol), N-Boc-valine (41 mg, 0.19mmol), and DIPEA (0.083 mL, 0.47 mmol) in DMF (20 mL) was added HATU (90mg, 0.236 mmol). The resulting solution was stirred at r.t. for 3 h. Thereaction mixture was partitioned between ethyl acetate and water, washedwith 1M HCl and brine, dried (MgSO₄), filtered and concentrated to yieldthe crude, BOC-protected product. This material was dissolved indichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred atr.t. for 3 h. The mixture was then concentrated and the residue waspurified by Gilson reverse phase HPLC (35-95% MeOH/H₂O, Aquasil C₁₈, 30min) and lyophilized. The residue (containing some formic acid from theHPLC) was partitioned between dichloromethane and 1M NaOH. The organicphase was dried (MgSO₄), filtered and concentrated to give 341 (18 mg,50% yield) as a 7:3 mixture of rotamers by ¹H NMR. ¹H NMR (DMSO-d₆)δ(ppm) ¹H: 8.73 (s, 1H); 8.57-8.51 (m, 2H); 8.36 (s, 0.3H); 8.32 (s,0.7H); 8.29-8.24 (m, 1H); 7.84-7.71 (m, 2H); 7.38 (t, J=8.8, 1H); 7.21(d, J=8.3, 1H); 6.66-6.64 (m, 1H); 6.59 (s, 1H); 4.90 (d, J=17.6, 0.3H);4.73 (d, J=15.6, 0.7H); 4.64 (d, J=17.1, 0.3H); 4.53 (d, J=15.6, 0.7H);3.73-3.39 (m, 5H); 3.25 (s, 2.2H); 3.22 (s, 1.1H); 2.58-2.52 (m, 1H);1.80-1.70 (m, 1H); 0.89-0.84 (m, 6H); 0.68-0.64 (m, 2H); 0.45-0.41 (m,2H). LRMS: (M+H) 607.5.

Examples 213 and 214N¹-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(3-(methylsulfonyl)phenyl)malonamide(345) andN¹-(3-fluoro-4-(2-(5-((N-(2-methoxyethyl)acetamido)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(3-(methylsulfonyl)phenyl)malonamide(346) Step 1: methyl3-(4-(2-(5-((tert-butoxycarbonyl(2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)-3-oxopropanoate(342)

To a solution of compound 126 (480 mg, 0.915 mmol) and DIPEA (479 μl,2.74 mmol) in DCM (9 ml) at room temperature was added methyl malonylchloride (196 μl, 1.83 mmol). The mixture was stirred for 18 h. Asaturated aqueous solution of ammonium chloride was added and theaqueous phase extracted twice with DCM. The combined organic layers weredried over anhydrous sodium sulfate and concentrated. The residue waspurified via Biotage (linear gradient 0-20%, methanol/dichloromethane;Snap 50 g column) to afford compound 342 (540 mg, 0.86 mmol, 94% yield)as a yellow oil. MS (m/z): 625.5 (M+H).

Step 2.3-(4-(2-(5-((tert-butoxycarbonyl(2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylamino)-3-oxopropanoicacid (343)

To a solution of compound 342 (540 mg, 0.864 mmol) in THF (12 ml) andwater (6 ml) was added LiOH monohydrate (363 mg, 8.64 mmol). The mixturewas stirred 48 h at room temperature and THF was removed under reducedpressure. The aqueous solution was diluted with water (10 ml) andacidified to pH 4 using 1N HCl. The suspension was filtered and theprecipitate was dried under high vacuum to afford compound 343 (485 mg,0.79 mmol, 92% yield) as a beige solid. MS (m/z): 611.5 (M+H).

Steps 3 and 4.N¹-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(3-(methylsulfonyl)phenyl)malonamide(345)

To a solution of compound 343 (120 mg, 0.197 mmol),3-methylsulfonylaniline hydrochloride (82 mg, 0.393 mmol) and DIPEA (172μl, 0.983 mmol) in DMF (4 ml) was added BOP reagent (261 mg, 0.59 mmol)and the mixture was stirred at room temperature for 18 h. A saturatedaqueous solution of ammonium chloride was added and the aqueous phaseextracted twice with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous sodium sulfate and the solventwas removed under reduced pressure. The residue was purified via Biotage(linear gradient 0-20%, methanol/dichloromethane; Snap 25 g column) toafford compound 344 as yellow solid (not characterized) which wasdissolved in DCM (10 ml) and treated with TFA (4.5 mL, 59 mmol). Themixture was stirred for 18 h at room temperature. The solvent wasremoved under reduced pressure, the residue was diluted with ethylacetate and the organic layer was extracted with 1N NaOH. The aqueousphase was extracted 3 times with ethyl acetate and the combined organiclayers were concentrated. The residue was purified via Biotage (lineargradient 0-30%, methanol/dichloromethane; Snap 50 g column) to affordcompound 345 (39 mg, 0.059 mmol, 29.9% yield) as a beige solid. ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 10.65 (s, 1H), 10.61 (s, 1H), 8.57 (d, J=1.6Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 8.24 (d,J=8.0 Hz, 1H), 7.92-7.85 (m, 3H), 7.66-7.60 (m, 2H), 7.51 (t, J=8.8 Hz,1H), 7.45 (dd, J=9.2, 1.6 Hz, 1H), 6.68 (dd, J=5.2, 0.8 Hz, 1H), 3.79(s, 2H), 3.57 (s, 2H), 3.41 (t, J=5.6 Hz, 2H), 3.24 (s, 3H), 3.21 (s,3H), 2.66 (t, J=5.6 Hz, 2H). MS (m/z): 664.5 (M+H).

Step 5.N¹-(3-fluoro-4-(2-(5-((N-(2-methoxyethyl)acetamido)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N³-(3-(methylsulfonyl)phenyl)malonamide(346)

A solution of compound 345 (18.5 mg, 0.028 mmol) in acetic anhydride(1.31 ml, 13.9 mmol) was stirred at room temperature for 60 h. Thesolvent was removed under reduced pressure and the residue wastriturated with water for 3 h. The solid suspension was filtered, theprecipitate was rinsed with water and dried under high vacuum to affordcompound 346 (6.4 mg, 9.07 μmol, 32.5%) as a beige solid. ¹H NMR (400MHz, DMSO-d₆) δ (ppm): mixture of rotamers, 10.64 (s, 1H), 10.60 (s,1H), 8.55-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.91-7.86 (m, 2H), 7.78 (td,J=8.8, 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.44 (dd,J=9.2, 1.6 Hz, 1H), 6.71-6.67 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.58-3.23(m, 14H), 3.21 (s, 3H), 2.13 and 2.05 (2s, 3H). MS (m/z): 706.5 (M+H).

Example 215N-((2-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)-N-(2-methoxyethyl)methanesulfonamide(349) Step 1:tert-Butyl(2-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(347)

To a solution of the aniline 46 (400 mg, 0.758 mmol) was addedtriphosgene (1125 mg, 5 eq, 3.79 mmol) and iPr₂NEt (490 mg, 5 eq, 3.79mmol) and the reaction mixture was stirred at RT for an hour.Cyclopropylamine (6103 mg, 141 eq, 107 mmol) was added and the reactionmixture was stirred at RT overnight. The mixture was concentrated thendiluted with DCM and washed with water. The organic phase was collected,dried over Na₂SO₄, filtered and evaporated. The residue was purified bycolumn chromatography (eluent 20% MeOH in EtOAc) to afford the desiredcompound 347 as a yellow oil (426 mg, 92% yield). MS (m/z)=611.4 (M+H).

Step 2:1-Cyclopropyl-3-(3-fluoro-4-(2-(54(2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(348)

To a solution of the 347 (426 mg, 0.698 mmol) in DCM (10 ml) was addedHCl in dioxane (0.7 ml, 4.01 eq, 2.80 mmol, 4M in dioxane) and thereaction mixture was stirred at RT for 3 hours. The mixture wad dilutedwith water and solid NaHCO₃ was added. The reaction mixture wasextracted well with EtOAc then the organic phase was collected, driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (eluent 25% MeOH in EtOAc to 50% MeOH in EtOAc) toafford the desired compound 348 as a yellow powder (211 mg, 59% yield).MS (m/z)=511.4 (M+H).

Step 3:N-((2-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)-N-(2-methoxyethyl)methanesulfonamide(349)

To a suspension of the amine 348 (61 mg, 0.119 mmol) in DCM (5 ml) wasadded methanesulfonyl chloride (20.53 mg, 1.5 eq, 0.179 mmol) andiPr₂NEt (46.3 mg, 3 eq, 0.358 mmol) and the reaction mixture was stirredat RT for 3 hours. The mixture was diluted with EtOAc then washed withsaturated NH₄Cl solution, saturated NaHCO₃ solution and brine. Theorganic phase was collected, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (eluent25% MeOH in EtOAc) to afford the desired compound 349 as a pale yellowsolid (34 mg, 48%). ¹H NMR (d₆ DMSO) 8.27 (s, 1H), 8.10 (d, J=5.48 Hz,1H), 7.53 (s, 1H), 7.25 (m, 1H), 6.95 (t, J=9.0 Hz, 1H), 6.76 (m, 1H),6.71 (s, 1H), 6.24 (d, J=5.48 Hz, 1H), 6.14 (s, 1H), 4.06 (s, 2H), 3.49(s, 3H), 2.72 (s, 3H), 2.63 (s, 3H), 2.12 (m, 3H), 0.23 (m, 2H), 0.00(s, 2H).

Example 216 Step 1:tert-butyl(2-(7-(4-(3-(2,4-difluorophenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(350)

To a solution of aniline 46 (500 mg, 0.948 mmol) in DCM (10 ml) wasadded 2,4-difluoro-1-isocyanatobenzene (441 mg, 3 eq, 2.84 mmol) and thereaction mixture was stirred at RT for 24 hours. The mixture wasconcentrated and purified via column chromatography (eluent 10% MeOH inEtOAc) to afford 350 (600 mg, 93%) as a white solid. MS (m/z)=683.7(M+H)

Step 2:1-(2,4-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(351)

To a solution of 350 (600 mg, 0.879 mmol) in DCM (15 ml) was added HClin dioxane (2 ml, 7.17 eq, 8 mmol, 4M in dioxane) and the reactionmixture was stirred at RT for 3 hours. The mixture wad diluted withwater and solid NaHCO₃ was added. The reaction mixture was extractedwith EtOAc then the organic phase was collected, dried over Na₂SO₄,filtered and concentrated. Trituration of the residue with EtOAcafforded the desired compound 351 as an off-white solid (314 mg, 61%yield). ¹H NMR (d_(o)-DMSO): 10.90 (s, 1H), 8.89 (s, 1H), 8.50 (d,J=5.48 Hz, 1H), 7.98 (m, 1H), 7.95 (s, 1H), 7.72 (m, 1H), 7.41 (m, 1H),7.28-7.20 (m,3H), 7.04 (m, 1H), 6.68 (d, J=5.28 Hz, 1H), 4.28 (s, 2H),3.92 (s, 3H), 3.61 (m, 2H), 3.27 (s, 3H), 3.13 (m, 2H).

Step 3: (S)-tert-butyl1-(((2-(7-(4-(3-(2,4-difluorophenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)(2-methoxyethyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate(352)

To a solution of the compound 351 (280 mg, 0.481 mmol) in DMF (10 ml)was added (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (209mg, 2 eq, 0.961 mmol), iPr₂NEt (0.252 ml, 3 eq, 0.1.442 mmol) and HATU(365 mg, 2 eq, 0.961 mmol) and the reaction mixture was stirredovernight. The reaction mixture was diluted with EtOAc and washed withwater, saturated NAHCO₃ solution then brine. The organic phase wascollected, dried over Na₂SO₄, filtered then concentrated. Purificationof the residue by column chromatography (eluent 20% MeOH in EtOAc)afforded the desired compound 352 as an off-white solid (200 mg, 53%yield). MS (m/z)=782.7 (M+H).

Step 4:(S)-2-amino-N-((2-(7-(4-(3-(2,4-difluorophenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl)-N-(2-methoxyethyl)-3-methylbutanamide(353)

To a suspension of the compound 352 (200 mg, 0.256 mmol) in DCM (10 ml)was added HCl in dioxane (0.7 ml, 10.95 eq, 2.80 mmol, 4M in dioxane)and the reaction mixture was stirred at RT for 3 hours. The mixture waddiluted with water and solid NaHCO₃ was added. The reaction mixture wasextracted with EtOAc then the organic phase was collected, dried overNa₂SO₄, filtered and concentrated. Purification of the residue by columnchromatography (eluent 30% MeOH in EtOAc) afforded the desired compound353 as pale yellow powder (155 mg, 89% yield). ¹H NMR (d₆-DMSO) 9.36 (s,1H), 8.60 (s, 1H), 8.49 (m, 1H), 8.01 (m, 1H), 7.87 (s, 1H), 7.71 (m,1H), 7.41 (t, J=8.99 Hz, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.02 (m, 1H),6.98 (s, 1H), 6.65 (d, J=5.09 Hz, 1H), 4.83 (d, J=15.65 Hz, 1H), 4.48(d, J=15.65 Hz, 1H), 3.81 (s, 1H), 3.80 (s, 2H), 3.40 (m, 1H),3.39-3.295 (m, 6H), 1.71 (m, 2H), 0.81 (m, 6H).

Example 217N1-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(2-fluorophenyl)malonamide(355) Step 1.tert-Butyl(2-(7-(2-fluoro-4-(3-(2-fluorophenylamino)-3-oxopropanamido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(354)

To a solution of aniline 46 (300 mg, 0.569 mmol), acid 2 (224 mg, 1.137mmol), and DIPEA (0.397 mL, 2.274 mmol) in DMF (15 mL) was added HATU(540 mg, 1.422 mmol). The reaction mixture was stirred for 16 h at rt,then partitioned between ethyl acetate and water; the organic layer wascollected, washed with water, 1M NaOH, and brine, dried (Na₂SO₄) thenfiltered and concentrated. The residue was purified by Biotage(eluent1-30% MeOH/EA, Silicycle 12 g column) to give 354 (230 mg, 0.325 mmol,57.2% yield) as a beige solid. TLC: R_(f)=0.35 (eluent 10% MeOH/EtOAc),

Step 2.N1-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(2-fluorophenyl)malonamide(355)

To a solution of 354 (230 mg, 0.325 mmol) in DCM (3 mL) was added TFA(0.5 mL). The reaction mixture was stirred at room temperature overnightthen concentrated. The residue was partitioned between EtOAc and NaHCO₃saturated solution. The organic layer was collected, dried andconcentrated. The residue was purified via Biotage (0-50% MeOH/EA; 10 gSNAP column) to afford a reddish solid which was purified again by flashcolumn chromatography (eluent MeOH/EA, 20-25%) to give a yellowish solidwhich was triturated with ether to afford the title compound 355 (80 mg,0.132 mmol, 40.5% yield) as an off-white solid. HNMR (dmso) d(ppm) 1H:10.53(s, 1H), 10.01(s, 1H), 8.47(d, 1H, J=5.5 Hz), 7.95(m, 1H),7.85-7.81(m, 2H), 7.46(t, 1H, J=8.8 Hz), 7.39(d, 1H, J=10.9 Hz),7.15-7.09(m, 2H), 6.91(s, 1H), 6.65(d, 1H, J=5.5 Hz), 3.81(s, 3H),3.72(s, 2H), 3.58(s, 2H), 3.35(t, 2H, J=5.6 Hz), 3.20(s, 3H), 2.64(t,2H, J=5.6 Hz). MS: 607.2 (MH)⁺.

Example 2182-fluoro-N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)benzamide(357) Step 1.tert-Butyl(2-(7-(2-fluoro-4-(2-fluorobenzamido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methyl(2-methoxyethyl)carbamate(356)

To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM (10 mL) at 0° C.was added DIPEA (0.199 mL, 1.137 mmol) and 2-fluorobenzoyl chloride (135mg, 0.853 mmol) and the suspension was stirred overnight at roomtemperature. The reaction mixture was concentrated and the residue waspartitioned between EtOAc and water. The organic layer was collected,dried and concentrated. The residue was purified using Biotage (eluentEtOAc, 25 g Silicycle HR column) to provide the title compound 356 (400mg, 0.616 mmol, quantitative yield) as a white solid.

MS: 650(MH)+.

Step 2.2-Fluoro-N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)benzamide(357)

A solution of of 356 (400 mg, 0.616 mmol) and TFA (0.047 mL, 0.616 mmol)in DCM (15 mL) was stirred overnight at room temperature thenconcentrated. The residue was partitioned between EtOAc and NaHCO₃saturated solution. The product was found in both layers. The layerswere combined and concentrated. The residue was extracted with MeOH andthe inorganic solid was filtered off. The filtrate was concentrated andthe residue was purified using Biotage (eluent MeOH/EtOAc, 10-50%, 25 gSilicycle column) to provide a solid that was triturated with a mixtureEtOAc/ether to afford 358 (40 mg, 0.073 mmol, 11.82% yield) as a whitesolid. HNMR: (dmso) d(ppm) 1H:10.77(s, 1H), 8.51(d, 1H, J=5.5 Hz),7.94-7.91(m, 2H), 7.68-7.63(m, 1H), 7.60-7.56(m, 2H), 7.49(t, 1H), J=8.8Hz), 7.36-7.30(m, 2H), 7.15(s, 1H), 6.70(d, 1H, J=5.5 Hz), 4.13(s, 2H),3.89(s, 3H),3.51(t, 2H, J=5.3 Hz), 3.26(s, 3H), 3.01(m, 2H). MS: 550(MH)⁺

Example 2191-Cyclopropyl-3-(3-fluoro-4-(2-(5-(morpholinomethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea(360) Step 1.4-((6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)morpholine(358)

To a suspension of carbaldehyde 321 (0.5 g, 1.265 mmol) in DCM (12.65ml) were added morpholine (0.220 ml, 2.53 mmol) and acetic acid (0.145ml, 2.53 mmol), and the mixture was stirred for 1 h at room temperaturebefore sodium triacetoxy borohydride (0.804 g, 3.79 mmol) was added.Stirring was continued overnight. The mixture was then partitionedbetween DCM and 1N NaOH. The phases were separated; the organic layerwas collected, dried over sodium sulfate and concentrated. The residuewas purified via Biotage (linear gradient 0-20%, MeOH/EtOAc; 10 g SNAPcolumn) to afford the title compound 358 (341 mg, 0.731 mmol, 57.8%yield) as a beige solid. MS: 467 (MH)+.

Step 2.3-Fluoro-4-(2-(5-(morpholinomethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)aniline(359)

A mixture of the nitro compound 358 (432 mg, 0.926 mmol), iron powder(440 mg, 7.87 mmol), and ammonium chloride (42.6 mg, 0.796 mmol) in amixture of water (3.00 mL) and ethanol (6 mL) was heated to 80° C. for30 min. The reaction mixture was then filtered while hot through a padof Celite. The filtrate was concentrated and the residue was purifiedusing Biotage (eluent 0-20% EtOAc/MeOH, 10 g SNAP column) to afford theamine 359 (136 mg, 0.312 mmol, 33.6% yield) as a white solid. MS: 437(MH)+.

Step 3.1-Cyclopropyl-3-(3-fluoro-4-(2-(5-(morpholinomethyl)pyridin-2-yl)thieno[3,2-d]pyridin-7-yloxy)phenyl)urea(360)

The solution of aniline 359 (136 mg, 0.312 mmol) and DIPEA (0.218 mL,1.246 mmol) in THF (6 mL) was cooled to 0° C., and then triphosgene(46.2 mg, 0.156 mmol) was added and the reaction mixture was stirred for1 h at 0° C. followed by an addition of cyclopropylamine (89 mg, 1.558mmol). The reaction mixture was stirred at r.t. for an additional 3 hrsthen concentrated, partitioned between water and ethyl acetate. A thicksolid was formed which was isolated by suction filtration, rinsed withwater and ethyl acetate, and dried in vacuo. This material was thenpurified using Gilson (eluent 20-95% MeOH/H₂O, 1 h) to give the titlecompound 360 (30 mg, 0.058 mmol, 18.53% yield) as a white solid. ¹HNMR(DMSO-d₆) d(ppm) ¹H:HNMR 9.16(s, br, 1H), 8.16(d, 1H, J=1.6 HZ), 8.11(d,1H, J=5.4 Hz), 7.91(s, 1H), 7.83(d, 1H, J=8.2 Hz), 7.46(dd, 1H, J1=2.1Hz, J2=8.2 Hz), 7.34(dd, 1H, J1=2.6 Hz, J2=13.9 Hz), 6.97-7.45(m, 2H),6.84-6.81(m, 1H), 6.23(d, 1H, J=4.7 Hz), 3.18(t, 4H), 3.14(s, 2H),2.15-2.12(m, 1H), 1.98(m, 4H), 0.23-0.19(m, 2H), 0.02-0.005(m, 2H). MS:520.4(MH)+.

Example 2201-(4-(2-(4-5,8,11-Trioxa-2-azadodecylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea(368) Step 1:4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)benzaldehyde(362)

Iodothienopyridine 361 (US 2006/0287343) (2.10 g, 5.05 mmol),4-formylphenylboronic acid (1.51 g, 10.1 mmol), andtetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) were dissolvedin dry dioxane (80 mL). Cesium fluoride (0.92 g, 6.1 mmol) and sodiumbicarbonate (2.12 g, 25.2 mmol) were dissolved in water (5 ml each) andadded to the reaction mixture, which was degassed with a stream of N₂,then heated to reflux for 3 h, cooled, and concentrated. The residue waspartitioned between ethyl acetate and water, resulting in a thickprecipitate. This was isolated by suction filtration and rinsed withwater and ethyl acetate to afford 362 (1.92 g, 96%). LRMS (M+H): 395.2

Step 2: NN-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-2-(2-(2-methoxyethoxy)ethoxy)ethanamine(364)

A suspension of 362 (0.90 g, 2.3 mmol), amine 363 (0.93 g, 5.7 mmol)[amine 363 has been synthesized according to the procedures used for thesynthesis of amines 322 (scheme 18) and 326 (scheme 20)] and acetic acid(0.26 ml, 4.6 mmol) in dichloromethane (50 ml) was stirred for 1 h atroom temperature. Then sodium triacetoxyborohydride (1.45 g, 6.85 mmol)was added and the mixture was stirred at r.t. for 16 h. A further amountof sodium triacetoxyborohydride (1.5 g) was then added, and stirringcontinued for 2 h. The reaction mixture was partitioned betweendichloromethane and 1N HCl. The organic phase was discarded. The aqueousphase was basified (pH=13) with 3M NaOH, and extracted withdichloromethane. The organic extract was dried over anhydrous sodiumsulfate, filtered, and concentrated to yield 364 (0.72 g, 58%) as ayellow solid. LRMS (M+H): 542.4

Step 3: tert-butyl4-(7-(2-fluoro-4-nitrophenoxy)thieno[3.2-b]pyridin-2-yl)benzyl(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate(365)

To a solution of 364 (0.72 g, 1.3 mmol) in dichloromethane (100 mL) atroom temperature was added DMAP (0.041 g, 0.33 mmol) and Boc₂O (0.58 g,2.7 mmol). The reaction mixture was stirred at room temperature for 2 hthen the mixture was washed sequentially with water, brine, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel chromatography (eluent EtOAc then 1% MeOH inEtOAc) to afford compound 365 (0.51 g, 60% yield). LRMS (M+H): 642.5

Step 4: tert-butyl4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-ylbenzyl(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate(366)

To a solution of 365 (0.49 g, 0.76 mmol) in MeOH (100 mL) was added irondust (0.43 g, 7.6 mmol) and ammonium chloride (0.12 g, 2.3 mmol) inwater (5 mL). The resulting mixture was heated to reflux for 4 h, thencooled, filtered through a celite pad and concentrated. The residue waspartitioned between dichloromethane and water; the organic phase wascollected, washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (eluent 2% MeOH in EtOAc) to give 366 (0.41 g, 88%yield). LRMS (M+H): 612.6

Step 5: tert-butyl4-(7-(2-fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamate(367)

To a solution of 366 (0.15 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g,0.61 mmol) in tetrahydrofuran (50 mL) at 0° C. was added triphosgene(0.029 g, 0.098 mmol) and the resulting solution was stirred for 1 h at0° C. 3-Amino-5-methylisoxazole (0.025 g, 0.25 mmol) was added and themixture was warmed to room temperature and stirred for 3 h, thenquenched with 1 mL of water and concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water; the organicphase was collected, washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by silica gel chromatography(eluent 2% MeOH in EtOAc) to give 367 (0.074 g, 4% yield).

Step 7:1-(4-(2-(4-5,8,11-trioxa-2-azadodecylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea(368)

To a solution of 367 (0.074 g, 0.10 mmol) in dichloromethane (50 mL) wasadded trifluoroacetic acid (1.0 mL). The reaction mixture was stirredfor 3 h at r.t. then concentrated and the residue was partitionedbetween dichloromethane and sat. NaHCO₃. The organic phase wascollected, washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by Gilson reverse phase HPLC(35-75% MeOH/H₂O, Aquasil C₁₈, 30 min) and lyophilized. The purifiedproduct (containing some formic acid from the HPLC) was partitionedbetween dichloromethane and 1M NaOH). The organic phase was collected,dried (MgSO₄), filtered and concentrated to give compound 368 (0.033 g,0.052 mmol, 52% yield).

¹H NMR (DMSO-d₆) δ(ppm) ¹H: 9.71 (s, 1H); 9.31 (s, 1H); 8.48 (d, J=5.5,1H); 8.01 (s, 1H); 7.82-7.79 (m, 2H); 7.73 (dd, J=13.1, 2.5,1H)7.46-7.41 (m, 3H); 7.28-7.26 (m, 1H); 6.60 (d, J=5.5, 1H); 6.54 (d,J=0.8, 1H); 3.75 (s, 2H); 3.51-3.45 (m, 8H); 3.41-3.35 (m, 2H); 3.20 (s,3H); 2.63 (t, J=5.7, 2H); 2.35 (d, J=0.6, 3H). LRMS (M+H): 636.5

Example 221N-(4-(7-(2-Fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide(371) Step 1:N-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide(369)

To a solution of 364 (0.50 g, 0.92 mmol) in dry tetrahydrofuran (50 mL)was added acetic anhydride (1.0 mL, 11 mmol). The reaction mixture wasstirred for 24 h at room temperature then concentrated. The residue waspartitioned between ethyl acetate and water; the organic phase wascollected, washed with sat. NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by silica gel chromatography(eluent EtOAc) giving 369 (0.36 g, 67% yield). LRMS (M+H): 584.4

Step 2:N-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide,(370)

To a solution of 369 (0.36 g, 0.62 mmol) in MeOH (100 mL) was added irondust (0.68 g, 12 mmol) and ammonium chloride (0.13 g, 2.5 mmol) in water(5 mL). The resulting mixture was heated to reflux for 4 h, then cooled,filtered through celite and concentrated. The residue was partitionedbetween dichloromethane and water; the organic phase was collected,washed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The product was purified by silica gel chromatography(eluent 2% MeOH in EtOAc) to give 370 (0.35 g, 100% yield). LRMS (M+H):554.4

Step 3:N-(4-(7-(2-fluoro-4-(3-(5-methylisoxazol-3-yl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide(371)

To a solution of 370 (0.14 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g,0.61 mmol) in tetrahydrofuran (50 mL) at 0° C. was added triphosgene(0.030 g, 0.10 mmol) and the resulting solution was stirred for 0.5 h at0° C. 3-Amino-5-methylisoxazole (0.074 g, 0.76 mmol) was added and themixture was warmed to room temperature and stirred for 3 h, thenquenched with 1 mL of water and concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water; the organicphase was collected, washed with brine, dried over MgSO₄, filtered andconcentrated. The product was purified by silica gel chromatography (10%MeOH in EtOAc), followed by Gilson reverse phase HPLC (35-65%acetonitrile/H₂O, Aquasil C₁₈, 30 min) and lyophilized. The residue(containing some formic acid from the HPLC) was partitioned betweendichloromethane and 1M NaOH. The organic phase was dried (MgSO₄),filtered and concentrated to give 371 (65 mg, 38% yield) as a 2:1mixture of rotamers by ¹H NMR. ¹H NMR (DMSO-d₆) δ (ppm) ¹H: 9.64 (s,1H); 9.19 (s, 1H); 8.50-8.48 (m, 1H); 8.04 (s, 0.4H); 8.01 (s, 0.6H);7.89 (d, J=8.2, 0.4H); 7.82 (d, J=8.2, 0.6H); 7.72 (dd, J=12.9, 2.5,1H); 7.45 (t, J=9.2, 1H); 7.33 (d, J=8.4, 2H); 7.27-7.24 (m, 1H);6.61-6.59 (m, 1H); 6.54 (d, J=0.8, 1H); 4.68 (s, 0.4H); 4.59 (s, 0.6H);3.52-3.38 (m, 12H); 3.21 (s, 1.8H); 3.20 (s, 1.2H); 2.35 (d, J=0.4, 3H);2.12 (s, 1.8H); 2.00 (1.2H). LRMS (M+H): 678.8

Example 222 2,2,2-Trifluoroethyl3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate(373) Step 1.4-(2-(5-((tert-Butoxycarbonyl(2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl2,2,2-trifluoroethyl methylcarbamate (372)

Diphosgene (0.017 ml, 0.143 mmol) was added to a solution of aniline 126(0.15 g, 0.286 mmol) in THF (2.86 ml) and the reaction mixture wasstirred vigorously for 2 hrs. To the reaction mixture was added2,2,2-trifluoroethanol (0.042 ml, 0.572 mmol) and a solution of DIPEA(0.100 ml, 0.572 mmol) in THF (2.86 ml). The reaction mixture wasstirred vigorously overnight, diluted with DCM, washed with saturatedammonium chloride solution, dried over anhydrous sodium sulfate andconcentrated to dryness. The residue was purified by flashchromatography (Biotage, Snap 10 column, gradient: 3% 10 CV, 3% to 5% 2CV, and 5% 10 CV MeOH in DCM) affording 372 (0.1097 g, 0.169 mmol, 59.0%yield) as light brown solid. m/z: 651.4 (M+H)⁺.

Step 2. 2,2,2-Trifluoroethyl3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate(373)

To a suspension of 372 (0.1097 g, 0.169 mmol) in DCM (1.0 ml) was addedTFA (1.0 ml, 12.98 mmol) and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated underreduced pressure, the residue dissolved in DCM, washed with IN NaOHsolution, water, dried over anhydrous sodium sulfate and concentratedunder reduced pressure affording 373 (0.0543 g, 0.097 mmol, 57.3% yield)as white solid. ¹H-NMR (DMSO-D₆, 400 MHz) 10.55 (s, 1H), 8.57 (s, 1H),8.52 (d, J=5.62 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.90 (d,J=8.10 Hz, 1H), 7.63 (d, J=9 Hz, 1H), 7.52 (d, J=13.5 Hz, 1H), 7.39 (t,J=9.0 Hz, 1H), 6.66 (d,J=6.7 Hz, 1H), 4.85 (q, J=9.0 Hz, 2H), 3.79 (s,2H), 3.41 (t, J=5.5 Hz, 2H), 3.24 (s, 3H), 2.66 (t, J=5.5 Hz, 2H). m/z:(M+H)⁺ 551.4.

Example 223N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)cyclopropanesulfonamide(376) Step 1: ethyl cyclopropylsulfonylcarbamate (374)

To a solution of cyclopropanesulfonamide (Li, J. et al; Synlett 2006, 5,725-728) (800 mg, 6.60 mmol) in acetone (25 ml) was added potassiumcarbonate (2.738 g, 3 eq, 19.81 mmol) and ethyl chloroformate (1.075 g,1.5 eq, 9.90 mmol) and the reaction mixture was stirred at RT overnight.The reaction mixture was poured into water and made acidic (pH 1) withcone HCl then extracted with EtOAc. The extract was collected, driedover Na₂SO₄, filtered and concentrated. Purification of the residue bycolumn chromatography (eluent 30% EtOAc in hexanes) afforded 374 as acolourless oil (800 mg, 63%). ¹H NMR (DMSO, d₆) 11.47 (s, 1H), 4.10 (q,J=10.27 Hz, 2H), 2.90 (m, 1H), 1.19 (t, J=7.24 Hz, 3H), 1.039 (m, 4H).

Step 2:tert-butyl(6-(7-(4-(3-(cyclopropylsulfonyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate(375)

To a solution of the amine 126 (500 mg, 0.953 mmol) in DME (4 ml) wasadded the carbamate 374 (460 mg, 2.5 eq, 2.383 mmol) and the reactionmixture was heated to 120° C. for 1 day. The mixture was cooled to RT,diluted with EtOAc and water and the organic phase was collected, driedover Na₂SO₄, filtered and concentrated. Purification of the residue bycolumn chromatography (eluent EtOAc to 50% Acetone in EtOAc) afforded375 as a brown oil (130 mg, 55%). MS (m/z)=672.5 (M+H)

Step 3:N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)cyclopropanesulfonamide(376)

To a solution of the 375 (140 mg, 0.208 mmol) in DCM (5 ml) was addedHCl in dioxane (0.5 ml, 2 mmol, 9.6 eq, 4M in dioxane) and the reactionmixture was stirred for 4 hours. The mixture was diluted with EtOAc,made basic with NaHCO₃ solution and extracted with EtOAc/acetone. Theorganic phase was collected and discarded. The aqueous phase wasconcentrated and the residue was suspended in a mixture of DCM andacetone. The solution phase was collected, dried with Na₂SO₄, filteredand concentrated to afford 376 as a beige solid after furthertrituration with Et₂O (yield 8 mg, 7%). ¹H NMR (DMSO-d6): 8.67 (s, 1H),8.56 (s, 1H), 8.47 (d, J=5.28, 1H), 8.27 (s, 1H), 8.19 (d, J=8.02 Hz,1H), 7.85 (m, 2H), 7.80 (s, 1H), 7.22 (m, 2H), 6.59 (d, J=5.28 Hz, 1H),3.76 (s, 2H), 3.40 (m, 2H), 3.20 (s, 3H), 2.76 (m, 1H), 2.60 (m, 2H),0.75 (m, 2H), 0.65 (m, 2H). LRMS(ESI): (calc.) 571.64 (found) 572.58(MH)⁺.

Additional compounds according to the present invention include those inTable 2.

TABLE 2 Cpd Ex Structure Characterization 377 224

1-(3-(dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm):1H: 8.50 (d, 1H, J = 5.5 Hz), 7.87 (s, 1H), 7.84 (s, 1H), 7.74 (dd, 1H,J1 = 2.4 Hz, J2 = 13.3 Hz), 7.62 (m, 1H), 7.44-7.26 (m, 4H), 6.93 (s,1H), 6.66 (d, 1H, J = 5.5 Hz), 3.89 (s, 3H), 3.74 (m, 2H), 3.38 (t, 2H,J = 5.6 Hz), 3.22 (s, 3H), 2.66 (m, 2H), 1.98 (m, 1H), 1.62 (d, 6H, J =13.3 Hz). LRMS(ESI): (calc.) 622.2 (found) 623.5 (MH)+ 378 225

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-o-tolylurea ¹H NMR (DMSO-d₆) δ (ppm): 1H: 9.37 (s, 1H),8.48 (d, J = 5.48 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.73 (m, 2H),7.40 (m, 1H), 7.21-7.12 (m, 3H), 6.93 (m, 2H), 6.64 (d, J = 5.48 Hz,1H), 3.87 (s, 3H), 3.72 (s, 2H), 3.36 (m, 2H), 3.21 (s, 3H), 2.65 (t, J= 5.48 Hz, 2H), 2.22 (s, 3H) LRMS(ESI): (calc.) 560.64 (found) 561.5(MH)+ 379 226

1-(3-fluoro-4-(2-(5((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea ¹H NMR(DMSO-d₆) δ (ppm): 9.56 (s, 1H), 9.03 (s, 1H), 8.55 (d, 1H, J = 7.3 Hz),8.48 (d, 1H, J = 5.3 Hz), 7.85 (s, 1H), 7.73 (dd, J1 = 13.1 Hz, J2 = 2.3Hz), 7.50-7.21 (m, 3H), 7.22 (d, 1H, J = 8.8 Hz), 6.92 (s, 1H), 6.64 (d,1H, J = 5.5 Hz), 3.87 (s, 3H), 3.72 (s, 2H), 3.36 (t, 2H, J = 5.7 Hz),2.65 (t, 2H, J = 5.7 Hz), 2.02 (s, br, 1H). LRMS(ESI): (calc.) 632.2(found) 633.5 (MH)+ 380 227

1-(2,5-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm):9.55 (s, 1H), 8.92 (s, 1H), 8.48 (m, 1H), 8.0 (m, 1H), 7.85 (s, 1H),7.72 (m, 1H), 7.42 (t, J = 8.9 Hz, 1H), 7.30-7.20 (m, 2H), 6.91 (s, 1H),6.81 (m, 1H), 6.64 (d, J = 5.48 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 2H),3.36 (t, J = 5.67 hz, 2H), 3.20 (s, 3H), 2.64 (t, J = 5.67 Hz, 2H).LRMS(ESI): (calc.) 582.60 (found) 583.5 (MH)+ 381 228

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-methoxyphenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 8.96 (s,1H), 8.59 (s, 1H), 8.47 (d, 1H, J = 5.5 Hz), 7.85 (s, 1H), 7.70 (dd, 1H,J1 = 2.3 Hz, J2 = 13.3 Hz), 7.38 (t, 1H, J = 9.0 Hz), 7.33- 7.31 (m,2H), 7.21-7.18 (m, 1H), 6.91 (s, 1H), 6.85- 6.83 (m, 2H), 6.63 (d, 1H, J= 5.3 Hz), 3.87 (s, 3H), 3.72 (s, 2H), 3.67 (s, 3H), 3.36 (t, 2H, J =5.6 Hz), 3.19 (s, 3H), 2.65 (t, 2H, J = 5.5 Hz). LRMS(ESI): (calc.)576.2 (found) 577.5 (MH)+ 382 229

1-(3-bromophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm):9.15 (s, 1H), 9.02 (s, 1H), 8.48 (d, J = 5.28 Hz, 1H), 7.86 (s, 1H),7.81 (m, 1H), 7.70 (m, 1H), 7.41 (t, J = 8.99 Hz, 1H), 7.31 (m, 1H),7.24 (m, 3H), 7.14 (m, 1H), 6.94 (s, 1H), 6.64 (d, J = 5.28 Hz, 1H),3.87 (s, 3H), 3.77 (s, 2H), 3.375 (t, J = 5.48 hz, 2H), 3.20 (s, 3H),2.69 (t, J = 5.48 Hz, 2H) LRMS(ESI): (calc.) 625.51 (found) 625.4/627.4(MH)+ 383 230

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆)δ (ppm): 9.35 (s, 1H), 9.29 (s, 1H), 8.47 (d, J = 5.48 Hz, 1H), 8.06 (m,1H), 7.84 (s, 1H), 7.70 (m, 1H), 7.59 (m, 2H), 7.41 (t, J = 8.99 Hz,1H), 7.25 (m, 1H), 6.91 (s, 1H), 6.63 (d, J = 5.48 Hz, 1H), 3.86 (s,3H), 3.72 (s, 2H), 3.35 (t, J = 5.67 Hz, 2H), 3.19 (s, 3H), 2.64 (t, J =5.67 Hz, 2H) LRMS(ESI): (calc.) 649.06 (found) 649.5 (M)+ 384 231

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 10.16 (s, br,1H), 9.94 (s, br, 1H), 8.52 (d, 1H, J = 5.4 Hz), 7.98-7.90 (m, 3H), 7.81(dd, 1H, J1 = 2.5 Hz, J2 = 13.2 Hz), 7.67-7.65 (m, 1H), 7.47- 7.42 (m,2H), 7.36-7.32 (m, 3H), 6.96 (s, 1H), 6.69 (d, 1H, J = 5.4 Hz), 3.92 (s,3H), 3.77 (s, 2H), 3.40 (t, 2H, J = 5.4 Hz), 3.35 (s, 3H), 2.69 (t, 2H,J = 5.2 Hz), 1.81 (s, 1H). LRMS(ESI): (calc.) 589.2 (found) 590.5 (MH)+385 232

4-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.16 (s, 1H),9.07 (s, 1H), 8.47 (d, J = 5.48 hz, 1H), 7.85 (s, 1H), 7.73 (m, 2H),7.70 (m, 1H), 7.45 (m, 2H), 7.41 (t, J = 8.99 hz, 1H), 7.22 (m, 1H),7.17 (s, 1H), 6.91 (s, 1H), 6.64 (d, J = 5.28 hz, 1H), 3.87 (s, 3H),3.73 (s, 2H), 3.36 (t, J = 5.67 Hz, 2H), 3.2 (s, 3H), 2.65 (t, J = 5.67Hz, 2H) LRMS(ESI): (calc.) 589.64 (found) 590.4 (MH)+ 386 233

N1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N3-(3-(oxazol-5-yl)phenyl)malonamide ¹H NMR (DMSO-d₆) δ(ppm): 10.55 (s, 1H), 10.35 (s, 1H), 8.47 (d, J = 5.48 Hz, 1H), 8.42 (s,1H), 8.0 (s, 1H), 7.83 (m, 2H), 7.61 (s, 1H), 7.53-7.39 (m, 5H), 6.92(s, 1H), 6,65 (d, J = 5.28 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 2H), 3.51 (s,2H), 3.34 (t, J = 6.26 Hz, 2H), 3.2 (s, 3H), 2.65 (t, J = 5.67 Hz, 2H).LRMS(ESI): (calc.) 655.70 (found) 656.6 (MH)+

Additional compounds according to the present invention include those inTable 3.

TABLE 3 Cpd Ex Structure Characterization 387 234

1-(3-(dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(6-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 9.10 (s, 1H),9.02 (s, 1H), 8.50 (d, 1H, J = 5.5 Hz), 8.32 (s, 1H), 8.10 (d, 1H, J =7.9 Hz), 7.89 (t, 1H, J = 7.9 Hz), 7.84 (d, 1H, J = 12.7 Hz), 7.74 (dd,1H, J = 2.6 Hz, J = 13.3 Hz), 7.62 (d, 1H, J = 8.0 Hz), 7.4-7.5 (m, 3H),7.33 (m, 1H), 7.26 (m, 1H), 6.62 (d, 1H, J = 5.7 Hz), 3.85 (s, 2H), 3.22(s, 3H), 2.72 (t, 2H, J = 5.5 Hz), 1.64 (s, 3H), 1.60 (s, 3H) LRMS(ESI):(calc.) 619.2 (found) 620.4 (MH)+ 388 235

1-(4-(2-(5-5,8,11-trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3- cyclopropylurea ¹HNMR (DMSO-d₆) δ (ppm): 8.80 (s, 1H); 8.57 (s, 1H); 8.51 (d, J = 5.5,1H); 8.31 (s, 1H); 8.23 (d, J = 8.0, 1H); 7.89 (dd, J = 8.0, 1.5, 1H);7.73 (dd, J = 13.5, 2.2, 1H); 7.38 (t, J = 9.0, 1H); 7.20 (d, J = 8.2,1H); 6.67 (d, J = 2.7, 1H); 6.64 (d, J = 5.5, 1H); 3.78 (s, 2H); 3.56-45(m, 12H); 3.41 (t, J = 5.7, 2H); 3.21 (s, 3H); 2.66 (d, J = 5.7, 2H);2.58-2.51 (m, 1H); 0.66- 0.62 (m, 2H); 0.44-0.41 (m, 2H). LRMS(ESI):(calc.) 595.7 (found) 596.4 (MH)+ 389 236

1-(4-(2-(5-5,8,11,14-tetraoxa-2-azapentadecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea ¹H NMR (DMSO-d₆) δ (ppm): 9.66 (s, 1H); 9.23(s, 1H); 8.57 (s, 1H); 8.52 (d, J = 5.3, 1H); 8.32 (s, 1H); 8.23 (d, J =8.0, 1H); 7.90 (dd, J = 8.2, 2.2, 1H); 7.74 (dd, J = 13.1, 2.5, 1H);7.47 (t, J = 9.0, 1H); 7.30-7.26 (m, 1H); 6.66 (d, J = 5.9, 1H); 6.56(d, J = 0.9, 1H); 3.78 (s, 2H); 3.52-3.47 (m, 12H); 3.40-3.36 (m, 2H);3.21 (s, 3H); 2.65 (t, J = 5.7, 2H); 2.37 (s, 3H). LRMS(ESI): (calc.)680.8 (found) 681.6 (MH)+ 390 237

1-(4-(2-(5-5,8,11-trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(3-(dimethylphosphoryl)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 9.16 (s, 1H),9.08 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.33(s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.93-7.84 (m, 2H), 7.77 (dd, J =12.8, 2.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49-7.41 (m, 2H), 7.37(dd, J = 10.8, 7.6 Hz, 1H), 7.31-7.26 (m, 1H), 6.67 (d, J = 5.6 Hz, 1H),3.80 (s, 2H), 3.53- 3.46 (m, 8H), 3.44-3.39 (m, 2H), 3.22 (s, 3H), 2.67(t, J = 5.6 Hz, 2H), 1.64 (d, J = 13.2 Hz, 6H). LRMS(ESI): (calc.)707.23 (found) 708.7 (MH)+ 391 238

1-(3-(dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-(2-methoxyethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm):9.12 (s, 1H), 9.05 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.6Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.92-7.83 (m, 2H), 7.77(dd, J = 13.2, 2.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 2H),7.37 (dd, J = 10.8, 7.0 Hz, 1H), 7.29 (dd, J = 8.8, 1.2 Hz, 1H), 6.67(d, J = 5.2 Hz, 1H), 3.79 (s, 2H), 3.52-3.40 (m, 6H), 3.24 (s, 3H), 2.66(t, J = 5.6 Hz, 2H), 1.64 (d, J = 13.2 Hz, 6H). LRMS(ESI): (calc.)663.21 (found) 664.4 (MH)+ 392 239

1-(3-fluoro-4-(2-(5-((2-(2- methoxyethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(5- methylisoxazol-3-yl)urea¹H NMR (DMSO-d₆) δ (ppm): 9.64 (s, 1H), 9.23 (bs, 1H), 8.58 (d, J = 1.6Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.0 Hz,1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (dd, J = 13.0, 2.4 Hz, 1H),7.47 (t, J = 8.8 Hz, 1H), 7.31-7.26 (m, 1H), 6.67 (d, J = 5.2 Hz, 1H),6.56 (s, 1H), 3.80 (s, 2H), 3.53-3.40 (m, 6H), 3.24 (s, 3H), 2.67 (t, J= 5.6 Hz, 2H), 2.38 (s, 3H). LRMS(ESI): (calc.) 592.19 (found) 593.5(MH)+ 393 240

N-((6-(7-(4-(3-(3-(dimethylphosphoryl)phenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)acetamide ¹H NMR (DMSO-d₆) δ (ppm):(mixture of rotamers) 9.22 (s, 1H), 9.14 (s, 1H), 8.56-8.48 (m, 2H),8.38-8.32 (2s, 1H), 8.29 and 8.23 (2d, J = 8.0 Hz, 1H), 7.87 (d, J =12.8 Hz, 1H), 7.82- 7.73 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.49-7.41(m, 2H), 7.40-7.33 (m, 1H), 7.29 (d, J = 10 Hz, 1H), 6.70-6.65 (m, 1H),7.71 and 4.59 (2s, 2H), 3.54-3.36 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.13and 2.05 (2s, 3H), 1.64 (d, J = 13.6 Hz, 6H). LRMS(ESI): (calc.) 661.19(found) 662.6 (MH)+ 394 241

1-(5-(dimethylphosphoryl)-2-fluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (MeOH-d₄) δ (ppm):two NH urea are missing, 8.73 (s, 1H), 8.62 (ddd, J = 12.9, 7.7, 1.9 Hz,1H), 8.49 (d, J = 5.3 Hz, 1H), 8.34 (bs, 1H, formate salt), 8.19 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 6.7 Hz, 1H), 7.78 (dd, J = 12.9,2.3 Hz, 1H), 7.55- 7.45 (m, 1H), 7.41-7.31 (m, 2H), 7.25 (dd, J = 8.9,1.4 Hz, 1H), 6.68 (d, J = 5.5 Hz, 1H), 4.34 (s, 2H), 3.70 (t, J = 5.0Hz, 2H), 3.35 (s, 3H), 3.30 (t, J = 5.1 Hz, 2H), 1.82 (d, J = 13.5 Hz,6H), one NH is missing. LRMS(ESI): (calc.) 637.64 (found) 638.5 (MH)+395 242

1-cyclopropyl-3-(2-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 8.56 (s, 1H);8.52 (d, J = 8.5, 1H); 8.30 (s, 1H); 8.25-8.18 (m, 2H); 7.89 (dd, J =8.0, 2.1, 1H); 7.34 (dd, J = 11.7, 2.5, 1H); 7.09 (dd, J = 8.8, 1.8,1H); 6.82 (d, J = 2.7, 1H); 6.69 (d, J = 5.5, 1H); 3.77 (s, 2H); 3.41(t, J = 5.7, 2H); 3.24 (s, 3H); 2.65 (t, J = 5.7, 2H); 2.56 (septet, J =3.3, 1H); 0.67- 0.62 (m, 2H); 0.43-0.40 (m, 2H). LRMS(ESI): (calc.)507.6 (found) 508.4 (MH)+ 396 243

1-cyclopropyl-3-(4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 8.59 (s, 1H),8.56 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.29 (s, !H), 8.22(d, J = 8.4 Hz, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 9.0Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 5.6 Hz, 1H), 6.56 (bs,1H), 3.77 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J =5.6 Hz, 2H), 2.58-2.50 (m 1H), 2.26 (bs, 1H), 0.68-0.60 (m, 2H),0.44-0.39 (m, 2H). LRMS(ESI): (calc.) 489.18 (found) 490.5 (MH)+ 397 244

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(4-methylthiazol-2-yl)urea ¹H NMR (DMSO-d₆)δ (ppm): 9.40 (s, 1H), one NH urea is missing, 8.58 (bs, 1H), 8.53 (d, J= 5.5 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.91 (dd, J =8.3, 1.7 Hz, 1H), 7.78 (dd, J = 13.0, 2.2 Hz, 1H), 7.47 (t, J = 9.0 Hz,1H), 7.35 (bd, J = 10.3, 1H), 6.67 (d, J = 5.3 Hz, 1H), 6.64 (s, 1H),3.81 (s, 2H), one CH2 is masked by water, 3.25 (s, 3H), 2.69 (t, J = 5.6Hz, 2H), 2.23 (s, 3H), one NH is missing. LRMS(ESI): (calc.) 564.65(found) 565.4 (MH)+ 398 245

1-(2-chloro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-fluoro-5- (trifluoromethyl)phenyl)urea ¹HNMR (DMSO-d₆) δ (ppm): 9.7 (d, J = 2.6 Hz, 1H), 9.03 (s, 1H), 8.65 (dd,J = 2.1 Hz, J = 7.3 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.54 (d, J = 5.4Hz, 1H), 8.32 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.23 (d, J = 8.2 Hz,1H), 7.89 (dd, J = 2.1 Hz, J = 8.2 Hz, 1H), 7.6 (d, J = 2.9 Hz, 1H),7.53 (dd, J = 8.5 Hz, J = 10.6 Hz, 1H), 7.44- 7.42 (m, 1H), 7.32 (dd, J= 2.6 Hz, J = 9.1 Hz, 1H), 6.74 (d, J = 5.5 Hz, 1H), 3.78 (s, 2H), 3.41(t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J = 5.8 Hz, 2H) m/z: (M +2) + 2 /2 323.7 (100%), (MH)+ 646.5 (32%) 399 246

1-(2-chloro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-cyclopropylurea ¹H NMR (DMSO-d₆) δ (ppm):8.56 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.29 (s, 1H), 8.25(d, J = 9.3 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.89 (dd, J= 2.1 Hz, J = 8.3 Hz, 1H), 7.50 (d, J = 2.9 Hz, 1H), 7.25 (dd, J = 2.9Hz, J = 9.2 Hz, 1H), 7.20 (d, J = 2.9 Hz, 1H), 6.69 (d, J = 5.3 Hz, 1H),3.77 (s, 2H), 3.40 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 2.65 (t, J = 5.8Hz, 2H), 2.59-2.55 (m, 1H), 0.67-0.66 (m, 2H), 0.44- 0.42 (m, 2H) m/z:(M + 2) + 2 /2 262.7 (100%), 263.5 (42%); (M + 1)+ 524.4 (50%), 526.4(20%) 400 247

3-(3-(4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)ureido)benzamide ¹H NMR(DMSO-d₆) δ (ppm): 9.02 (s, 1H), 8.97 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H),8.51 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H),7.96-7.87 (m, 3H), 7.65 (dd, J = 8.0, 2.0 Hz, 1H), 7.61 (d, J = 8.8 Hz,2H), 7.47 (d, J = 7.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.26 (d, J = 8.8 Hz,2H), 6.65 (d, J = 5.6 Hz, 1H), 3.80 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H),3.24 (s, 3H), 2.67 (t, J = 5.6 Hz, 2H). LRMS(ESI): (calc.) 568.19(found) 569.5 (MH)+ 401 248

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((3-methoxypropylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 8.77 (s, 1H);8.63 (d, J = 1.4, 1H); 8.52 (d, J = 5.3, 1H); 8.35 (s, 1H); 8.28 (d, J =8.0, 1H); 7.97 (dd, J = 8.2, 2.0, 1H); 7.73 (dd, J = 13.7, 2.3, 1H);7.38 (t, J = 9.2, 1H); 7.20 (d, J = 8.6, 1H); 6.65 (d, J = 5.3, 1H);6.60 (d, J = 2.4, 1H); 3.94 (s, 2H); 3.38 (t, J = 6.3, 2H); 3.21 (s,3H); 2.72-2.68 (m, 2H); 2.55 (septet, J = 3.1, 1H); 1.74 (quintet, J =6.9, 2H); 0.68-0.63 (m, 2H); 0.45-0.40 (m, 2H); LRMS(ESI): (calc.) 521.6(found) 522.4 (MH)+ 402 249

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzoic acid ¹H NMR (DMSO-d₆) δ (ppm):9.85-9.68 (bs, 1H), 9.68-9.57 (bs, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.53(d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.21 (s,1H), 8.16 (s, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.80 (dd, J = 13.2,2.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45(t, J = 9.2 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H),6.68 (d, J = 5.6 Hz, 1H), 3.84 (s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 3.25(s, 3H), 2.71 (t, J = 5.6 Hz, 2H). LRMS(ESI): (calc.) 587.16 (found)588.5 (MH)+ 403 250

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzenesulfonamide ¹H NMR (DMSO-d₆) δ(ppm): 9.27 (s, 1H); 9.24 (s, 1H); 8.57 (d, J = 1.6, 1H); 8.53 (d, J =5.5, 1H); 8.32 (s, 1H); 8.23 (d, J = 8.2, 1H); 8.09 (s, 1H); 7.89 (dd, J= 8.0, 2.0, 1H); 7.77 (dd, J = 13.1, 2.3, 1H); 7.58 (d, J = 8.0, 1H);7.52-7.44 (m, 3H); 7.38 (s, 2H); 7.38-7.31 (m, 1H); 6.67 (d, J = 5.5,1H); 3.78 (s, 2H); 3.41 (t, J = 5.7, 2H); 3.24 (s, 3H); 2.65 (t, J =5.7, 2H); 2.33 (br s, 1H). LRMS(ESI): (calc.) 622.7 (found) 623.3 (MH)+404 251

3-(3-(4-(2-(5-5,8,11-trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)ureido)benzamide ¹H NMR(DMSO-d₆) δ (ppm): 9.35 (s, 1H); 9.12 (s, 1H); 8.60 (d, J = 1.5, 1H);8.53 (d, J = 5.5, 1H); 8.33 (s, 1H); 8.25 (d, J = 8.0, 1H); 7.94 (s,1H); 7.91 (s, 2H); 7.77 (dd, J = 13.3, 2.5, 1H); 7.64 (dd, J = 8.0, 1.4,1H); 7.49-7.43 (m, 2H); 7.38- 7.33 (m, 2H); 7.29-7.26 (m, 1H); 6.68 (d,J = 5.3, 1H); 3.86 (s, 2H); 3.52- 3.49 (m, 6H); 3.43-3.40 (m, 2H); 3.22(s, 3H); 2.75-2.70 (m, 2H). LRMS(ESI): (calc.) 674.7 (found) 675.5 (MH)+405 252

methyl 3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzoate ¹H NMR (DMSO-d₆) δ (ppm): 9.14(s, 1H), 9.12 (s, 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.53 (d, J = 5.6 Hz,1H), 8.32 (s, 1H), 8.25-8.20 (m, 2H), 7.90 (dd, J = 8.0, 2.0 Hz, 1H),7.77 (dd, J = 13.2, 2.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.60 (dt, J = 8.0,1.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.32-7.27 (m, 1H), 6.67 (d, J = 5.6 Hz,1H), 3.86 (s, 3H), 3.78 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H),2.65 (t, J = 5.6 Hz, 2H), 2.32 (bs, 1H). LRMS(ESI): (calc.) 601.18(found) 602.5 (MH)+ 406 253

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)-N-methylbenzamide ¹H NMR (DMSO-d₆) δ(ppm): 9.16 (s, 1H), 9.03 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.53 (d, J= 5.9 Hz, 1H), 8.44-8.40 (m, 1H), 8.36 (s, 1H), 8.27 (d, J = 8.3 Hz,1H), 7.96- 90 (m, 2H), 7.78 (dd, J = 13.2, 2.4 Hz, 1H), 7.62 (d, J = 6.8Hz, 1H), 7.49- 7.42 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 8.8Hz, 1H), 6.68 (d, J = 5.4 Hz, 1H), 3.89 (s, 2H), 3.45 (t, J = 5.4 Hz,2H), 3.26 (s, 3H), 2.89- 2.75 (m, 5H). LRMS(ESI): (calc.) 600.20 (found)601.5 (MH)+ 407 254

(R)-1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(tetrahydrofuran-3-yl)urea ¹H NMR (DMSO-d₆)δ (ppm): 8.83 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 5.4 Hz,1H), 8.41 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.04 (dd, J = 8.3, 2.4 Hz,1H), 7.72 (dd, J = 13.7, 2.4 Hz, 1H), 7.39 (t, J = 9.3 Hz, 1H),7.18-7.14 (m, 1H), 6.69-6.64 (m, 2H), 4.25- 4.18 (m, 1H), 4.16 (s, 2H),3.83-3.68 (m, 3H), 3.55 (t, J = 5.4 Hz, 2H), 3.50 (dd, J = 8.8, 3.4 Hz,1H), 3.30 (s, 3H), 3.08- 3.02 (m, 2H), 2.18-2.09 (m, 1H), 1.78-1.70 (m,1H) (presumably a mono-TFA salt) LRMS(ESI): (calc.) 537.2 (found) 538.3(MH)+ 408 255

(S)-1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(tetrahydrofuran-3-yl)urea (DMSO-d6) d (ppm)1H: 8.77 (s, 1H); 8.57 (s, 1H); 8.51 (d, J = 5.4, 1H); 8.31 (s, 1H);8.22 (d, J = 8.3, 1H); 7.89 (dd, J = 8.3, 1.5, 1H); 7.70 (dd, J = 13.7,2.4, 1H); 7.38 (t, J = 8.8, 1H); 7.17-7.14 (m, 1H); 6.64 (d, J = 5.4,1H); 6.61 (s, 1H); 4.23-4.21 (m, 1H); 3.82-3.68 (m, 3H); 3.79 (s, 2H);3.54- 3.48 (m, 1H); 3.41 (t, J = 5.4, 2H); 3.24 (s, 3H); 2.66 (t, J =5.4, 2H); 2.16- 2.11 (m, 1H); 1.76-1.72 (m, 1H). LRMS(ESI): (calc.)537.2 (found) 538.4 (MH)+ 409 256

3-(3-(3-fluoro-4-(2-(5-((N-(2- methoxyethyl)acetamido)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)ureido)benzamide ¹H NMR(DMSO-d₆) δ (ppm): 9.09 (s, 1H), 8.93 (s, 1H), 8.60-8.48 (m, 2H),8.40-8.18 (m, 2H), 7.92 (bs, 2H), 7.84-7.73 (m, 2H), 7.64 (d, J = 7.3Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.37 (d, J= 7.8 Hz, 1H), 7.33 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.73-6.64 (m,1H), 4.71 and 4.59 (2s, 2H), 3.55- 3.40 (m, 4H), 3.24 and 3.21 (2s, 3H),2.13 and 2.05 (2s, 3H). LRMS(ESI): (calc.) 628.67 (found) 629.5 (MH)+410 257

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide ¹H NMR (DMSO-d₆)δ (ppm): 8.74 (s, 1H); 8.53-8.50 (m, 2H); 8.34 (s, 0.3H), 8.31 (s,0.7H); 8.27 (d, J = 8.3, 0.3H); 8.21 (d, J = 8.3, 0.7H); 7.80-7.70 (m,2H), 7.37 (t, J = 8.8, 1H), 7.20 (d, J = 8.8, 1H); 6.66-6.63 (m, 2H),6.59 (s, 1H); 4.75 (s, 0.6H); 4.60 (s, 1.4H); 3.55-3.45 (m, 14H); 3.40(t, J = 4.9, 2H); 3.21 (s, 3H); 2.56-2.50 (m, 1H); 2.14 (s, 2.2H); 2.06(s, 0.8H); 0.67-0.64 (m, 2H); 0.44-0.40 (m, 2H). Mixture of rotamers,7:3 by 1H NMR. LRMS(ESI): (calc.) 681.8 (found) 704.5 (MNa)+ 411 258

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(1-methyl-1H-pyrazol-3- yl)urea ¹H NMR(DMSO-d₆) δ (ppm): 9.32 (bs, 1H), 9.07 (s, 1H), 8.57 (d, J = 1.4 Hz,1H), 8.52 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H),7.90 (dd, J = 8.1, 2.2 Hz, 1H), 7.78 (dd, J = 13.3, 2.5 Hz, 1H), 7.55(d, J = 2.3 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.27- 7.23 (m, 1H), 6.66(dd, J = 5.5, 0.8 Hz, 1H), 6.23 (d, J = 2.2, 1H), 3.79 (s, 2H), 3.74 (s,3H), 3.41 (t, J = 5.7 Hz, 2H), 3.32 (s, 1H), 3.24 (s, 3H), 2.66 (t, J =5.7 Hz, 2H). LRMS(ESI): (calc.) 547.6 (found) 548.4 (MH)+ 412 259

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)-N,N- dimethylbenzamide ¹H NMR (DMSO-d₆)δ (ppm): 9.17 (s, 1H), 9.00 (s, 1H), 8.58 (d, J = 1.2 Hz, 1H), 8.53 (d,J = 5.8 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.90 (dd, J =8.0, 2.0 Hz, 1H), 7.76 (dd, J = 13.2, 2.4 Hz, 1H), 7.58 (t, J = 1.2 Hz,1H), 7.48-7.42 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.28 (dt, J = 8.8, 1.2Hz, 1H), 7.01 (dt, J = 7.6, 1.2 Hz, 1H), 6.67 (dd, J = 5.6, 0.8 Hz, 1H),3.79 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H), 2.99 (s, 3H), 2.92(s, 3H), 2.66 (t, J = 5.6 Hz, 2H). LRMS(ESI): (calc.) 614.21 (found)615.5 (MH)+ 413 260

N-((6-(7-(2-fluoro-4-(3-(3-(methylsulfonyl)phenyl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2- methoxyethyl)acetamide ¹H NMR(DMSO-d₆) δ (ppm): mixture of rotamers, 9.30 (bs, 1H), 9.23 (bs, 1H),8.56-8.49 (m, 2H), 8.37 and 8.33 (2s, 1H), 8.29 and 8.23 (2d, J = 8.2Hz, 1H), 8.18 (t, J = 1.8 Hz, 1H), 7.82-7.67 (m, 3H), 7.62- 7.52 (m,2H), 7.47 (t, J = 9.0 Hz, 1H), 7.34-7.28 (m, 1H), 6.71-6.66 (m, 1H),4.71 and 4.59 (2s, 2H), 3.53-3.41 (m, 4H), 3.24 (s, 3H), 3.21 (s, 3H),2.13 and 2.05 (2s, 3H). LRMS(ESI): (calc.) 663.74 (found) 664.4 (MH)+414 261

1-cyclobutyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 8.77 (s, 1H),8.56 (d, J = 1.8 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.28 (s, 1H), 8.20(d, J = 7.9 Hz, 1H), 7.89 (dd, J = 1.9 Hz, J = 8.2 Hz, 1H), 7.68 (dd, J= 2.3 Hz, J = 10.1 Hz, 1H), 7.36 (t, J = 10.1 Hz, 1H), 7.15 (m, 1H),6.36 (d, J = 5.4 Hz, 1H), 6.60 (J = 7.8 Hz, 1H), 4.13 (m, 1H), 3.77 (s,2H), 3.52 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H), 3.20 (t, J = 5.5 Hz, 2H),2.22-2.17 (m, 2H), 1.89-1.85 (m, 2H), 1.64- 1.58 (m, 2H) m/z: (M + 2) +2 /2 261.7 (100%), (M + 1)+ 522.5 (5%). 415 262

3-(3-(3-fluoro-4-(2-(5-((N-(2- methoxyethyl)acetamido)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)-N,N- dimethylbenzamide ¹HNMR (DMSO-d₆) δ (ppm): (mixture of rotamers) 9.12 (s, 1H), 8.95 (s, 1H),8.56-8.48 (m, 2H), 8.38-8.26 (m, 2H), 8.23 (d, J = 8.0 Hz, 1H),7.82-7.72 (m, 3H), 7.58 (s, 1H), 7.50-7.41 (m, 2H), 7.36 (t, J = 8.0 Hz,1H), 7.28 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.68 (d, J =5.6 Hz, 1H), 4.71 and 4.59 (2s, 2H), 3.53-3.40 (m, 4H), 3.24 and 3.21(2s, 3H), 2.98 and 2.93 (2s, 6H), 2.13 and 2.05 (2s, 3H). LRMS(ESI):(calc.) 656.22 (found) 657.6 (MH)+ 416 263

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-isopropylurea ¹H NMR (DMSO-d₆) δ (ppm): 8.90(s, 1H), 8.55 (d, 1H, J = 1.6 Hz), 8.49 (d, 1H, J = 5.5), 8.29 (s, 1H),8.20 (d, 1H, J = 8.0 Hz), 7.87 (dd, 1H, J1 = 2.2 Hz, J2 = 8.3 Hz), 7.71(dd, 1H, J1 = 2.3 Hz, J2 = 3.5 Hz), 7.34 (t, 1H, J = 9.0 Hz), 7.14-7.11(m, 1H), 6,61 (d, 1H, J = 5.5 Hz), 6.36 (d, 1H, J = 7.4 Hz), 3,76 (m,3H), 3.39 (t, 2H, J = 5.6 Hz), 3.22 (s, 3H), 2.62 (t, 2H, J = 5.7 Hz),1.09 (s, 3H), 1.08 (s, 3H). LRMS(ESI): (calc.) 509.2 (found) 510.4 (MH)+417 264

1-(2,4-difluorophenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea ¹H NMR (DMSO-d₆) δ (ppm): 9.38 (s, 1H),8.69 (d, 1H, J = 1.6 Hz), 8.62 (dd, 1H, J1 = 0.4 Hz, J2 = 2.3 Hz), 8.53(d, 1H, J = 5.4 Hz), 8.40 (s, 1H), 8.35 (d, 1H, J = 7.8 Hz), 8.04-7.99(m, 2H), 7.74 (dd, 1H, J1 = 2.6 Hz, J2 = 13.1 Hz), 7.44 (t, 1H, J = 9.0Hz), 7.35-7.29 (m, 1H), 7.25-7.22 (m, 1H), 7.08-7.04 (m, 1H), 6,68 (dd,1H, J1 = 0.8 Hz, J2 = 5.3 Hz), 4.22 (s, 2H), 3.57 (t, 2H, J = 5.2 Hz),3.30 (s, 3H), 3.12 (m, 2H) (presumably a mono-TFA salt) LRMS(ESI):(calc.) 579.2 (found) 580.4 (MH)+ 418 265

1-(4-(2-(5-(1,3-dioxan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-cyclopropylurea ¹H NMR (DMSO-d₆) δ(ppm): 8.78 (s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 5.7 Hz, 1H),8.37 (s, 1H), 8.31 (dd, J = 8.2, 0.6 Hz, 1H), 7.94 (dd, J = 8.4, 2.0 Hz,1H), 7.74 (dd, J = 13.6, 2.4 Hz, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.21(bd, J = 9.6 Hz, 1H), 6.72 (d, J = 4.9 Hz, 1H), 6.63-6.57 (m, 1H), 5.68(s, 1H), 4.23- 4.15 (m, 2H), 3.99 (td, J = 12.1, 2.5 Hz, 2H), 2.59-2.52(m, 1H), 2.11- 1.97 (m, 1H), 1.53-1.45 (m, 1H), 0.69-0.62 (m, 2H),0.46-0.40 (m, 2H). LRMS(ESI): (calc.) 506.55 (found) 507.4 (MH)+ 419 266

methyl (6-(7-(4-(3-(3-carbamoylphenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate ¹H NMR (DMSO-d₆) δ (ppm): 9.11 (s,1H), 8.95 (s, 1H), 8.53 (d, J = 5.5 Hz, 2H), 8.34 (s, 1H), 8.25 (d, J =8.2 Hz, 1H), 7.94 (bs, 1H), 7.92 (t, J = 1.9 Hz, 1H), 7.85-7.77 (m, 1H),7.77 (dd, J = 13.3, 2.5 Hz, 1H), 7.67- 7.62 (m, 1H), 7.52-7.42 (m, 2H),7.37 (t, J = 7.8 Hz, 1H), 7.36 (bs, 1H), 7.31-7.25 (m, 1H), 6.68 (d, J =5.4 Hz, 1H), 4.54 (s, 2H), 3.64 (bs, 3H), 3.44 (bs, 4H), 3.22 (s, 3H).LRMS(ESI): (calc.) 644.67 (found) 645.5 (MH)+ 420 267

methyl (6-(7-(2-fluoro-4-(3-(3-(methylsulfonyl)phenyl)ureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2- methoxyethyl)carbamate ¹H NMR(DMSO-d₆) δ (ppm): 9.28 (s, 1H), 9.20 (s, 1H), 8.54 (d, J = 5.5 Hz, 2H),8.35 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.18 (t, J = 1.8 Hz, 1H),7.86-7.77 (m, 1H), 7.77 (dd, J = 13.3, 2.5 Hz, 1H), 7.73-7.67 (m, 1H),7.59 (t, J = 7.7 Hz, 1H), 7.55 (tt, J = 7.6, 1.6 Hz, 1H), 7.47 (t, J =9.0 Hz, 1H), 7.34-7.28 (m, 1H), 6.68 (d, J = 5.3 Hz, 1H), 4.54 (s, 2H),3.64 (bs, 3H), 3.44 (bs, 4H), 3.22 and 3.21 (2s, 6H). LRMS(ESI): (calc.)679.74 (found) 680.3 421 268

ethyl (6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate ¹H NMR (DMSO-d₆) δ (ppm): 8.70 (s,1H), 8.54 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J =8.4 Hz, 1H), 7.81 (d, J = 8.0, 1H), 7.73 (dd, J = 13.6, 2.8 Hz, 1H),7.38 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.64 (dd, J = 5.2,0.8 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 4.13-4.03 (m, 2H),3.45 (s, 4H), 3.22 (s, 3H), 2.59-2.52 (m, 1H), 1.26-1.08 (m, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). LRMS(ESI): (calc.) 579.20 (found) 580.5(MH)+ 422 269

cyclopentyl 3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate ¹H NMR (DMSO-d₆) δ (ppm): 9.98 (s,1H), 8.63 (s, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.28 (d, J =7.8 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 12.5 Hz, 1H), 7.45(t, J = 9.1 Hz, 1H), 7.34 (d, J = 9.1 Hz, 1H), 6.65 (d, J = 5.8 Hz, 1H),5.12 (s, 1H), 3.98 (s, 2H), 3.50- 3.48 (m, 2H), 3.27 (s, 3H), 2.87 (m,2H), 1.89- 1.88 (m, 2H), 1.70-1.60 (m, 6H) m/z: (M + 2) + 2 /2 269.2(100%), (M + 1)+ 537.5 (9%) 423 270

cyclohexyl 3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate ¹H NMR (DMSO-d₆) δ (ppm): 10.01 (s,1H), 8.58 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J =8.0 Hz, 1H), 7.92 (m, 1H), 7.64 (m, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.38(d, J = 8.3 Hz, 1H), 6.65 (d, 1H), 4.65 (m, 1H), 3.84 (m, 2H), 3.44 (m,2H), 3.24 (s, 3H), 2.72 (m, 2H), 1.89 (m 2H), 1.72 (m, 2H), 1.51 (m,1H), 1.43-1.39 (m, 4H), 1.22 (m, 1H) m/z: (M + 2) + 2 /2 276.2 (100%),(M + 1)+ 551.5 (31%) 424 271

cyclobutyl 3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate ¹H NMR (DMSO-d₆) δ (ppm): 10.08 (s,1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.22 (d, J = 5.4 Hz, 1H), 8.30 (s, 1H),8.22 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 13.0 Hz, 1H), 7.44 (t, J = 8.7Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 5.4 Hz, 1H), 4.94 (m,1H), 3.83 (s, 2H), 3.42 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 2.70 (t, J =5.9 Hz, 2H), 2.30 (m, 2H), 2.09- 2.01 (m, 2H), 1.78-1.71 (m, 1H),1.62-1.57 (m, 1H) m/z: (M + 2) + 2 /2 262.2 (100%), (M + 1)+ 523.4 (31%)425 272

N-(4-(2-(5-5,8,11-trioxa-2-azadodecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide ¹H NMR(DMSO-d₆) δ (ppm): 10.39 (s, 1H); 10.00 (s, 1H); 8.55 (d, J = 1.6, 1H);8.50 (d, J = 5.3, 1H); 8.31 (s, 1H); 8.22-8.18 (m, 1H); 7.91-7.86 (m,2H); 7.64-7.60 (m, 2H); 7.51-7.42 (m, 2H); 7.17-7.11 (m, 2H); 6.63 (s, J= 5.5, 1H); 3.77 (s, 2H); 3.50- 3.43 (m, 6H); 3.49 (s, 3H); 3.39-3.37(m, 2H); 2.66-2.62 (m, 2H); 1.45 (s, 4H). LRMS(ESI): (calc.) 717.8(found) 718.5 (MH)+ 426 273

N1-(3-carbamoylphenyl)-N3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)malonamide ¹H NMR (DMSO-d₆) δ (ppm): 10.62 (s,1H), 10.37 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.36 (d, J =7.6 Hz, 1H), 8.09-8.05 (m, 2H), 7.96 (s, 1H), 7.90 (dd, J = 12.8, 2.0Hz, 1H), 7.81-7.76 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.4Hz, 1H), 7.46 (dd, J = 9.2, 2.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.36(s, 1H), 6.71 (d, J = 5.2 Hz, 1H), 4.22 (s, 2H), 3.59 (t, J = 5.2 Hz,2H), 3.54 (s, 2H), 3.31 (s, 3H), 3.14-3.08 (m, 2H) (presumably amono-TFA salt). LRMS(ESI): (calc.) 628.19 (found) 629.5 (MH)+ 427 274

N1-cyclopropyl-N3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)malonamide ¹H NMR (DMSO-d₆) δ (ppm): 10.11 (s,1H), 8.16 (d, 1H, J = 1.4 Hz), 8.10 (d, 1H, J = 5.3 Hz), 7.91 (s, 1H),7.83-7.81 (m, 2H), 7.50-7.44 (m, 2H) 7.08 (t, 1H, J = 9.0 Hz), 7.06-7.00(m, 1H), 6,26 (d, 1H, J = 5.5 Hz), 3.37 (s, 2H), 3.00 (t, 2H, J = 5.7Hz), 2.88 (s, 3H), 2.81 (s, 2H), 2.24 (t, 2H, J = 4.5 Hz), 0.24-0.22 (m,2H), 0.03-0.01 (m, 2H). LRMS(ESI): (calc.) 549.1 (found) 550.4 (MH)+ 428275

N1-cyclobutyl-N3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)malonamide ¹H NMR (DMSO-d₆) δ (ppm): 10.50 (s,1H), 8.57 (s, 1H), 8.52 (d, 1H, J = 5.4 HZ), 8.40 (d, 1H, J = 7.8 Hz),8.33 (s, 1H), 8.24 (d, 1H, J = 8.2 Hz), 7.91-7.68 (m, 2H), 7.49 (t, 1H,J = 9.0 Hz), 7.42 (d, 1H, J = 8.2 Hz), 6.67 (d, 1H, J = 4.9 Hz), 4.20(m, 1H), 3.78 (s, 2H), 3.41 (t, 2H), 3.24 (s, 3H), 3.23 (s, 2H), 2.65(t, 3H), 2.17 (m, 2H), 1.90 (m, 2H), 1.64 (m, 2H). LRMS(ESI): (calc.)563.2 (found) 564.5 (MH)+ 429 276

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-N-(2-methoxyethyl)methanesulfonamide ¹H NMR (DMSO-d₆) δ(ppm): 8.71 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H),8.35 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 2.0 Hz, 1H),7.73 (dd, J = 13.6, 2.4 Hz, 1H), 7.38 (t, J = 8.8 Hz, 1H), 7.20 (d, J =8.8 Hz, 1H), 6.65 (dd, J = 5.6, 0.8 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H),4.48 (s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.38-3.30 (m, 2H, hidden underwater peak), 3.20 (s, 3H), 3.06 (s, 3H), 2.59-2.52 (m, 1H), 0.69-0.62(m, 2H), 0.46-0.40 (m, 2H). LRMS(ESI): (calc.) 585.15 (found) 586.55(MH)+ 430 277

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-2-(2-methoxyethoxy)-N-(2- methoxyethyl)acetamide ¹H NMR(DMSO-d₆) δ (ppm): 8.76 (s, 1H); 8.54-8.51 (m, 2H); 8.36 (s, 0.3H); 8.32(s, 0.7H); 8.28 (d, J = 8.2, 0.3H); 8.23 (d, J = 8.2, 0.7H); 7.84-7.76(m, 1H); 7.72 (dd, J = 13.5, 2.5, 1H); 7.36 (t, J = 9.0, 1H); 7.20 (d, J= 9.0, 1H); 6.65-6.60 (m, 2H); 4.67 (s, 0.6H); 4.61 (s, 1.4H); 4.31 (s,1.5H); 4.21 (s, 0.5H); 3.60-3.15 (m, 14H); 2.55 (septet, J = 3.5, 1H);0.68- 0.62 (m, 2H); 0.45-0.41 (m, 2H). (mixture of two rotamers, approx7:3 ratio by NMR. LRMS(ESI): (calc.) 623.2 (found) 624.5 (MH)+ 431 278

1-(4-(2-(5-5,8,11,14-tetraoxa-2-azapentadecylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(3-(methylsulfonyl)phenyl)urea ¹H NMR (DMSO-d₆)δ (ppm): 9.34 (s, 1H), 9.26 (s, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.53 (d,J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.18 (t, J =1.9 Hz, 1H), 7.90 (dd, J = 8.2, 2.2 Hz, 1H), 7.77 (dd, J = 13.3, 2.4 Hz,1H), 7.70 (dt, J = 8.4, 1.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.55 (dt,J = 7.6, 1.5 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.34-7.28 (m, 1H), 6.67(dd, J = 5.5, 0.8 Hz, 1H), 3.80 (s, 2H), 3.54-3.46 (m, 12H), 3.42-3.38(m, 2H), 3.31 (bs, 1H), 3.21 and 3.208 (2s, 6H), 2.66 (t, J = 5.7 Hz,2H). LRMS(ESI): (calc.) 753.86 (found) 754.7 (MH)+ 432 279

N-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)-2-hydroxy-N-(2-methoxyethyl)acetamide ¹H NMR (DMSO-d₆) δ(ppm): (mixture of rotamers), 8.69 (s, 1H), 8.53-8.48 (m, 2H), 8.34 and8.31 (2s, 1H), 8.27 and 8.22 (2d, J = 8.0 Hz, 1H), 7.81-7.74 (m, 1H),7.71 (dd, J = 13.2, 2.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.18 (d, J =8.8 Hz, 1H), 6.62 (d, J = 4.8 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H),4.80-4.58 (m, 3H), 4.22 and 4.12 (2d, J = 5.6 Hz, 2H), 3.49-3.38 (m,4H), 3.21 and 3.19 (2s, 3H), 2.57-2.50 (m, 1H), 0.67-0.60 (m, 2H),0.44-0.38 (m, 2H). LRMS(ESI): (ca1c.) 565.18 (found) 566.5 (MH)+

Additional compounds according to the present invention include those inTable 4.

TABLE 4 Cpd Ex Structure and Characterization 433 280

1-(4-(2-(4-5,8,11-trioxa-2-azadodecylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(3-(dimethylphosphoryl)phenyl)urea ¹H NMR (DMSO-d6) δ(ppm): 9.14 (s, 1H), 9.07 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.03 (s,1H), 7.90-7.81 (m, 2H), 7.77 (dd, J = 13.2, 2.4 Hz, 1H), 7.64 (d, J =8.0 Hz, 1H), 7.50-7.41 (m, 3H), 7.36 (dd, J = 11.2, 7.6 Hz, 1H), 7.29(d, J = 8.8 Hz, 1H), 6.62 (d, J = 5.6 Hz, 1H), 3.77 (s, 2H), 3.53-3.46(m, 6H), 3.44-3.36 (m, 2H), 3.22 (s, 3H), 2.66 (t, J = 5.6 Hz, 2H), 1.64(d, J = 13.2 Hz, 6H). LRMS(ESI): (calc.) 706.24 (found) 354.3 (M + 2/2)434 281

N-(4-(2-(4-5,8,11-trioxa-2-azadodecylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide ¹H NMR(DMSO-d₆) δ (ppm): 10.42 (s, 1H); 10.02 (s, 1H); 8.50 (d, J = 5.5, 1H);8.02 (s, 1H); 7.91 (dd, J = 13.1, 2.2, 1H); 7.83 (d, J = 8.2, 2H);7.65-7.62 (m, 2H); 7.53-7.44 (m, 4H); 7.18-7.13 (m, 2H); 6.60 (d, J =5.5, 1H); 3.77 (s, 2H); 3.52-3.44 (m, 8H); 3.42-3.39 (m, 2H); 3.22 (s,3H); 2.65 (t, J = 5.7, 2H); 1.48-1.45 (m, 4H). LRMS(ESI): (calc.) 716.8(found) 717.6 (MH)+ 435 282

N-(4-(2-(4-(2-acetyl-5,8,11-trioxa-2-azadodecyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide ¹H NMR (DMSO-d₆) δ (ppm): 10.42 (s, 1H); 10.02 (s, 1H);8.51 (d, J = 5.5, 0.4H); 8.50 (d, J = 5.5, 0.6H); 8.06 (s, 0.4H); 8.04(s, 0.6H); 7.94-7.82 (m, 3H); 7.66-7.62 (m, 2H); 7.54-7.44 (m, 2H); 7.35(d, J = 8.2, 2H); 7.18-7.13 (m, 2H); 6.62-6.59 (m, 1H); 4.70 (s, 0.7H);4.60 (s, 1.3H); 3.55-3.40 (m, 12H); 3.23 (s, 3H); 2.13 (s, 2.1H); 2.03(s, 0.9H); 1.46 (s, 4H). LRMS(ESI): (calc.) 758.8 (found) 391.2 (M + H +Na/2)+ 436 283

1-(4-(2-(4-5,8,11-trioxa-2-azadodecylphenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(5-methylisoxazol-3-yl)urea ¹H NMR (DMSO-d₆) δ (ppm):9.71 (s, 1H); 9.31 (s, 1H); 8.48 (d, J = 5.5, 1H); 8.01 (s, 1H);7.82-7.79 (m, 2H); 7.73 (dd, J = 13.1, 2.5, 1H)7.46-7.41 (m, 3H);7.28-7.26 (m, 1H); 6.60 (d, J = 5.5, 1H); 6.54 (d, J = 0.8, 1H); 3.75(s, 2H); 3.51-3.45 (m, 8H); 3.41-3.35 (m, 2H); 3.20 (s, 3H); 2.63 (t, J= 5.7, 2H); 2.35 (d, J = 0.6, 3H). LRMS(ESI): (calc.) 635.7 (found)636.5 (MH)+

Additional compounds according to the present invention include those inTable 5

TABLE 5 Cpd Ex Structure and Characterization 437 284

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea hydrochloride (DMSO) d(ppm) 1H: 9.55 (br, 2H), 9.38(br, 1H), 8.82 (s, 1H), 8.72 (d, J = 6.0 Hz, 1H), 8.47 (s, 1H), 8.45 (d,J = 8.4 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 13.5, 2.1 Hz,1H), 7.44 (t, J = 9.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.97-6.92 (m,1H), 6.82 (br, 1H), 4.35-4.20 (m, 2H), 3.66 (t, J = 5.1 H, 2H), 3.32 (s,3H), 3.19- 3.11 (m, 2H), 2.60-2.52 (m, 1H), 0.69-0.62 (m, 2H), 0.45-0.39(m, 2H). 439 286

3-(3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureido)benzamide hydrochloride(DMSO) d(ppm) 1H: 9.75 (s, 1H), 9.39 (br, 3H), 8.79 (d, J = 1.8 Hz, 1H),8.67 (d, J = 6.0 Hz, 1H), 8.45 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.18(dd, J = 8.1, 2.4 Hz, 1H), 7.94 (br, 2H), 7.81 (dd, J = 13.5, 2.7 Hz,1H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.53-7.46 (m, 2H), 7.39-7.27 (m,3H), 6.89 (d, J = 5.7 Hz, 1H), 4.40-4.21 (m, 2H), 3.65 (t, J = 5.1 Hz,2H), 3.32 (s, 3H), 3.20-3.12 (m, 2H). 440 287

1-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(3-(methylsulfonyl)phenyl)urea hydrochloride (DMSO) d(ppm) 1H: 9.73 (s,1H), 9.70 (s, 1H), 9.30 (br, 2H), 8.77 (s, 1H), 8.64 (d, J = 5.7 Hz,1H), 8.44 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.18-8.14 (m, 2H), 7.80(dd, J = 13.5, 2.7 Hz, 1H), 7.69- 7.67 (m, 1H), 7.61-7.43 (m, 3H), 7.30(d, J = 9.3 Hz, 1H), 6.84 (d, J = 5.7 Hz, 1H), 4.30-4.25 (m, 2H), 3.64(t, J = 5.1 Hz, 2H), 3.32 (s, 3H), 3.21 (s, 3H), 3.19-3.12 (m, 2H). 441288

1-(3-fluoro-4-(2-(5((2-methoxyethylamino)methyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3- isopropylurea(DMSO) d(ppm) 1H: 8.70 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H), 7.89 (s, 1H),7.71 (dd, J = 2.4, 13.8 Hz, 1H), 7.37 (t, J = 9.0 Hz, 1H), 7.15- 7.10(m, 1H), 6.96 (s, 1H), 6.65 (d, J = 5.1 Hz, 1H), 6.17 (d, J = 7.8 Hz,1H), 3.92 (s, 3H), 3.83-3.72 (m, 1H), 3.77 (s, 2H), 3.41 (t, 5.4 Hz,2H), 3.25 (s, 3H), 2.70 (t, J = 5.4 Hz, 2H), 1.11 (d, J = 6.6 Hz, 6H).442 289

1-cyclopropyl-3-(3-fluoro-4-(2-(5-((2-(2-methoxyethoxy)ethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea (DMSO) d(ppm) 1H: 9.00 (s, 1H), 8.58 (d, J= 1.8 Hz, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 7.90 (dd, J = 8.1, 1.8 Hz, 1H), 7.74 (dd, J = 13.5, 2.1, 1H),7.38 (t, J = 8.7 Hz, 1H), 7.22 (d, J = 9.9 Hz, 1H), 6.84 (s, 1H), 6.64(d, J = 5.7 Hz, 1H), 3.79 (s, 2H), 3.54-3.40 (m, 6H), 3.24 (s, 3H), 2.66(t, J = 5.7 Hz, 2H), 2.57-2.51 (m, 1H), 0.68-0.61 (m, 2H), 0.45-0.40 (m,2H).

Pharmaceutical Compositions

In some embodiments, the invention provides pharmaceutical compositionscomprising a compound according to the invention and a pharmaceuticallyacceptable carrier, excipient, or diluent. Compositions of the inventionmay be formulated by any method well known in the art and may beprepared for administration by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In some embodiments, compositions of theinvention are administered intravenously in a hospital setting. In someembodiments, administration may be by the oral route.

The characteristics of the carrier, excipient or diluent will depend onthe route of administration. As used herein, the term “pharmaceuticallyacceptable” means a non-toxic material that is compatible with abiological system such as a cell, cell culture, tissue, or organism, andthat does not interfere with the effectiveness of the biologicalactivity of the active ingredient(s). Thus, compositions according tothe invention may contain, in addition to the inhibitor, diluents,fillers, salts, buffers, stabilizers, solubilizers, and other materialswell known in the art. The preparation of pharmaceutically acceptableformulations is described in, e.g., Remington's Pharmaceutical Sciences,18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

The active compound is included in the pharmaceutically acceptablecarrier, excipient or diluent in an amount sufficient to deliver to apatient a therapeutically effective amount without causing serious toxiceffects in the patient treated. The effective dosage range of apharmaceutically acceptable derivative can be calculated based on theweight of the parent compound to be delivered. If the derivativeexhibits activity in itself, the effective dosage can be estimated asabove using the weight of the derivative, or by other means known tothose skilled in the art.

Inhibition of VEGF Receptor Signaling

In some embodiments the invention provides a method of inhibiting VEGFreceptor signaling in a cell, comprising contacting a cell in whichinhibition of VEGF receptor signaling is desired with an inhibitor ofVEGF receptor signaling according to the invention. Because compounds ofthe invention inhibit VEGF receptor signaling, they are useful researchtools for in vitro study of the role of VEGF receptor signaling inbiological processes.

In some embodiments, inhibiting VEGF receptor signaling causes aninhibition of cell proliferation of the contacted cells.

ASSAY EXAMPLES Inhibition of VEGF Activity

The following protocol was used to assay the compounds of the invention.

Assay Example 1 In Vitro Receptor Tyrosine Kinase Assay (VEGF ReceptorKDR)

This test measures the ability of compounds to inhibit the enzymaticactivity of recombinant human VEGF receptor enzymatic activity.

A 1.6-kb cDNA corresponding to the catalytic domain of VEGFR2 (KDR)(Genbank accession number AF035121 amino acid 806 to 1356) is clonedinto the Pst I site of the pDEST20 Gateway vector (Invitrogen) for theproduction of a GST-tagged version of that enzyme. This constuct is usedto generate recombinant baculovirus using the Bac-to-Bac™ systemaccording to the manucfacturer's instructions (Invitrogen).

The GST-VEGFR2806-1356 protein is expressed in Sf9 cells (Spodopterafrugiperda) upon infection with recombinant baculovirus construct.Briefly, Sf9 cells grown in suspension and maintained in serum-freemedium (Sf900 II supplemented with gentamycin) at a cell density ofabout 2×106 cells/ml are infected with the above-mentioned viruses at amultiplicity of infection (MOI) of 0.1 during 72 hours at 27° C. withagitation at 120 rpm on a rotary shaker. Infected cells are harvested bycentrifugation at 398 g for 15 min. Cell pellets are frozen at −80° C.until purification is performed.

All steps described in cell extraction and purification are performed at4° C. Frozen Sf9 cell pellets infected with the GST-VEGFR2806-1356recombinant baculovirus are thawed and gently resuspended in Buffer A(PBS pH 7.3 supplemented with 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64 and 0.5 mM DTT)using 3 ml of buffer per gram of cells. Suspension is Dounce homogenizedand 1% Triton X-100 is added to the homogenate after which it iscentrifuged at 22500 g, 30 min., 4° C. The supernatant (cell extract) isused as starting material for purification of GST-VEGFR2806-1356.

The supernatant is loaded onto a GST-agarose column (Sigma) equilibratedwith PBS pH 7.3. Following a four column volume (CV) wash with PBS pH7.3 +1% Triton X-100 and 4 CV wash with buffer B (50 mM Tris pH 8.0, 20%glycerol and 100mM NaCl), bound proteins are step eluted with 5 CV ofbuffer B supplemented with 5 mM DTT and 15 mM glutathion.GST-VEGFR2806-1356 enriched fractions from this chromatography step arepooled based on U.V. trace i.e. fractions with high O.D.280. FinalGST-VEGFR2806-1356 protein preparations concentrations are about 0.7mg/ml with purity approximating 70%. Purified GST-VEGFR2806-1356 proteinstocks are aliquoted and frozen at −80° C. prior to use in enzymaticassay.

Inhibition of VEGFR/KDR is measured in a DELFIA™ assay (Perkin Elmer).The substrate poly(Glu4,Tyr) is immobilized onto black high-bindingpolystyrene 96-well plates. The coated plates are washed and stored at4° C. During the assay, the enzyme is pre-incubated with inhibitor andMg-ATP on ice in polypropylene 96-well plates for 4 minutes, and thentransferred to the coated plates. The subsequent kinase reaction takesplace at 30° C. for 10-30 minutes. ATP concentrations in the assay are0.6 uM for VEGFR/KDR (2× the Km). Enzyme concentration is 5 nM. Afterincubation, the kinase reactions are quenched with EDTA and the platesare washed. Phosphorylated product is detected by incubation withEuropium-labeled anti-phosphotyrosine MoAb. After washing the plates,bound MoAb is detected by time-resolved fluorescence in a GeminiSpectraMax reader (Molecular Devices). Compounds are evaluated over arange of concentrations and IC50's (concentration of compounds giving50% inhibition of enzymatic activity) are determined. The results areshown in Table 6. In the table, “a” indicates inhibitory activity at aconcentration of less than 250 nanomolar; “b” indicates inhibitoryactivity at a concentration ≧250 but <500 nanomolar, “c” indicatesinhibitory activity at ≧500 but <1000 nanomolar; and “d” indicatesinhibitory activity ≧1000 nanomolar.

Assay Example 2 VEGF-Dependent Erk Phosphorylation

Cells and growth factor: HUVEC cells were purchased from Cambrex BioScience Walkersville, Inc and cultured according to the vendor'sinstructions. The full-length coding sequence of VEGF₁₆₅ was clonedusing the Gateway Cloning Technology (Invitrogen) for baculovirusexpression Sf9 cells. VEGF₁₆₅ was purified from conditioned media usinga NaCl gradient elution from a HiTrap heparin column (GE Healthcare LifeSciences) followed by an imidazole gradient elution from a HiTrapchelating column (GE Healthcare Life Sciences), then buffer stored inPBS supplemented with 0.1% BSA and filter sterilized

Cell assays: Cells were seeded at 8000 cells/well of a 96 wells plateand grown for 48 hours. Cells were then grown overnight in serum andgrowth factor-free medium and exposed for 1.5 h to compounds dilutions.Following a 15 min incubation in medium, VEGF₁₆₅ (150 ng/ml) cells werelysed in ice-cold lysis buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 1.5 mMMgCl₂, 1% Triton X-100, 10% glycerol) containing 1 mM 4-(2aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 μM sodiumorthovanadate, 1 mM sodium fluoride, 10 μg/mL leupeptin, 10 μg/mLaprotinin, 1 μg/mL pepstatin and 50 μg/mL Na-p-tosyl-L-lysinechloromethyl ketone hydrochloride and processed as Western blots todetect anti-phospho ERK1/2 (T202/Y204) (Cell Signaling Technologies).

Western blot analysis: lysates samples from single treatment wells wereseparated on 5-20% SDS-PAGE gels and immunobloting was performed usingImmobilon polyvinylidene difluoride membranes (Amersham) according tothe manufacturer's instructions. The blots were washed in Tris-bufferedsaline with 0.1% Tween 20 detergent (TBST) and probed for antibodiesagainst phospho-Thr202/Tyr204-ERK (Cell signaling technologies.Chemiluminescence detection (Amersham, ECL plus) was performed accordingto the manufacturer's instructions using a Storm densitometer (GEHealthcare; 800 PMT, 100 nM resolution) for imaging and densitometryanalysis. Values of over the range of dilution were used to prepare IC₅₀curves using a 4-parameter fit model. These curves were calculated usingGraFit 5.0 software. The results are shown in Table 6. In the table, “a”indicates inhibitory activity at a concentration of less than 250nanomolar; “b” indicates inhibitory activity at a concentration ≧250 but<500 nanomolar, “c” indicates inhibitory activity at ≧500 but <1000nanomolar; and “d” indicates inhibitory activity ≧1000 nanomolar.

TABLE 6 VEGF- VEGFR2 dependent Erk IC50 phosphorylation Compound (mM)IC50 (mM)

a a

a a

a a

a a

a a

a a

a a

a a

a a

a a

b

a

a

d a

a a

b a

d a

a a

c a

a a

a a

a a

a a

a a

a a

b a

a a

a a

c a

a a

a a

a a

a a

a a

a

a a

Assay Example 3 In Vivo Solid Tumor Disease Model

This test measures the capacity of compounds to inhibit solid tumorgrowth.

Tumor xenografts are established in the flank of female athymic CD1 mice(Charles River Inc.), by subcutaneous injection of 1×106 U87, A431 orSKLMS cells/mouse. Once established, tumors are then serially passageds.c. in nude mice hosts. Tumor fragments from these host animals areused in subsequent compound evaluation experiments. For compoundevaluation experiments female nude mice weighing approximately 20 g areimplanted s.c. by surgical implantation with tumor fragments of ˜30 mgfrom donor tumors. When the tumors are approximately 100 mm3 in size(˜7-10 days following implantation), the animals are randomized andseparated into treatment and control groups. Each group contains 6-8tumor-bearing mice, each of which is ear-tagged and followedindividually throughout the experiment.

Mice are weighed and tumor measurements are taken by calipers threetimes weekly, starting on Day 1. These tumor measurements are convertedto tumor volume by the well-known formula (L+W/4)3 4/3π. The experimentis terminated when the control tumors reach a size of approximately 1500mm³. In this model, the change in mean tumor volume for a compoundtreated group/the change in mean tumor volume of the control group(non-treated or vehicle treated)×100 (AT/AC) is subtracted from 100 togive the percent tumor growth inhibition (% TGI) for each test compound.In addition to tumor volumes, body weight of animals is monitored twiceweekly for up to 3 weeks

Assay Example 4 In vivo Choroidal Neovascularization (CNV) Model

This test measures the capacity of compounds to inhibit CNV progression.CNV is the main cause of severe vision loss in patients suffering fromage-related macular degeneration (AMD).

Male Brown-Norway rats (Japan Clea Co., Ltd.) were used in thesestudies.

Rats were anesthetized by intraperitoneal injection of pentobarbital,and the right pupil was dilated with 0.5% tropicamide and 0.5%phenylephrine hydrochloride. The right eye received 6 laser burnsbetween retinal vessels using a slit lamp delivery system of Green laserPhotocoagulator (Nidex Inc., Japan), and microscope slide glass withHealon™ (AMO Inc) used as a contact lens. The laser power was 100 or 200mW for 0.1 second and spot diameter was 100 μm. At the time of laserburn, bubble production was observed, which is an indication of ruptureof Bruch's membrane which is important for CNV generation.

Rats were divided into the groups based on their body weight using SASsoftware (SAS institute Japan, R8.1) after laser irradiation (Day 0).After animals were anesthetized, and the right pupil dilated (as abovementioned), the right eye of the animal received the compound or vehicleby an injection (10 μL/eye) at doses of 30 nmol/eye on Day 3. Thecompounds were dissolved or suspended in CBS, PBS, or other adequatevehicles before injection.

On Day 10, the animals were anesthetized with ether, and high molecularweight fluorescein isothiocyanate (FITC)-dextran (SIGMA, 2×10⁶ MW) wasinjected via a tail vein (20 mg/rat). About 30 min after FITC-dextraninjection, animals were euthanized by ether or carbon dioxide, and theeyes were removed and fixed with 10% formaline neutral buffer solution.After over 1 hour of fixation, RPE-choroid-sclera flat mounts wereobtained by removing cornea, lens and retina from the eyeballs. The flatmounts were mounted in 50% glycerol on a microscope slide, and theportion burned by laser was photographed using a fluorescence microscope(Nikon Corporation, excitation filter: 465-495 nm, absorption filter:515-555 nm). The CNV area was obtained by measurement ofhyper-fluorescence area observed on the photograph using Scion image.

The average CNV area of 6 burns was used as an individual value of CNVarea, and the average CNV area of compound treated group was comparedwith that of the vehicle-treated group. Results with some compounds ofthe present invention are shown in Table 7 and are indicated as % ofinhibition of CNV progression (“A” indicates greater than or equal to60% inhibition, and “B” indicates ≧40% to <60% inhibition).

TABLE 7 Inhibition Cpd. No. of CNV (EX. No.) progression 315(202) A323(203) A 324(204) B 331(205) B 333(207) A 335(209) B 341(212) A348(215) B 349(215) A 351(216) B 387(235) B 390(238) B 392(240) B397(245) B 403(251) A 413(261) A 414(262) B 419(267) B 434(282) A

1. A compound selected from the group consisting of

and hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof.
 2. The compound according to claim 1, wherein the compound is


3. The compound according to claim 1, wherein the compound is


4. The compound according to claim 1, wherein the compound is


5. The compound according to claim 1, wherein the compound is


6. The compound according to claim 1, wherein the compound is


7. The compound according to claim 1, wherein the compound is


8. The compound according to claim 1, wherein the compound is


9. The compound according to claim 1, wherein the compound is


10. A composition comprising a compound according to claim 1, and a pharmaceutically aceeptable carrier.
 11. The composition according to claim 10, wherein the compound is


12. The composition according to claim 10, wherein the compound is


13. The composition according to claim 10, wherein the compound is


14. The composition according to claim 10, wherein the compound is


15. The composition according to claim 10, wherein the compound is


16. The composition according to claim 10, wherein the compound is


17. The composition according to claim 10, wherein the compound is


18. The composition according to claim 10, wherein the compound is


19. A method of treating an opthalmic disease, condition or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a composition thereof.
 20. The method according to claim 19, wherein the compound is


21. The method according to claim 19, wherein the compound is


22. The method according to claim 19, wherein the compound is


23. The method according to claim 19, wherein the compound is


24. The method according to claim 19, wherein the compound is


25. The method according to claim 19, wherein the compound is


26. The method according to claim 19, wherein the compound is


27. The method according to claim 19, wherein the compound is 